Notice of Award RESEARCH PROJECT COOPERATIVE AGREEMENT _ Federal Award Date: 03/06/2019 Department of Health and Human Services National Institutes of Health
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Grant Number: 1U19AI142759-01 FAIN: U19A1142759
Principal Investigator(s): RICHARD J. WHITLEY, MD
Project Title: Antiviral Drug Discovery and Development Center (AD3C)
OOA.OO UNIVERSITY OF ALABAMA AT BIRMINGHAM 1720 2nd Avenue South, AB1170 Birmingham, AL 352940111
Award e-mailed to: OSP-NGA@mail.ad.uab.edu
Period Of Performance: Budget Period: 03/07/2019 — 02/29/2020 Project Period: 03/07/2019 — 02/29/2024
Dear Business Official:
The National Institutes of Health hereby awards a grant in the amount of $7,500,000 (see “Award Calculation” in Section | and “Terms and Conditions” in Section II) to UNIVERSITY OF ALABAMA AT BIRMINGHAM in support of the above referenced project. This award is pursuant to the authority of 42 USC 241 31 USC 6305 42 CFR 52 and is subject to the requirements of this statute and regulation and of other referenced, incorporated or attached terms and conditions.
Acceptance of this award including the “Terms and Conditions” is acknowledged by the grantee when funds are drawn down or otherwise obtained from the grant payment system.
Each publication, press release, or other document about research supported by an NIH award must include an acknowledgment of NIH award support and a disclaimer such as “Research reported in this publication was supported by the National |nstitute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number U19A1142759. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Prior to issuing a press release concerning the outcome of this research, please notify the NIH awarding IC in advance to allow for coordination
Award recipients must promote objectivity in research by establishing standards that provide a reasonable expectation that the design, conduct and reporting of research funded under NIH awards will be free from bias resulting from an Investigator's Financial Conflict of Interest (FCO!), in accordance with the 2011 revised regulation at 42 CFR Part 50 Subpart F. The Institution shall submit all FCO! reports to the NIH through the eRA Commons FCO! Module. The regulation does not apply to Phase | Small Business Innovative Research (SBIR) and Small Business Technology Transfer (STTR) awards. Consult the NIH website http://grants.nih.gov/grants/policy/coi/ for a link to the regulation and additional important information.
If you have any questions about this award, please contact the individual(s) referenced in Section WV.
Sincerely yours,
NIHPaged001
=>
Vandhana Khurana Grants Management Officer NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Additional information follows
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SECTION I - AWARD DATA — 1U19AI142759-01
Award Calculation (U.S. Dollars)
Salaries and Wages $158,059 Fringe Benefits $50,812 Personnel Costs (Subtotal) $208,871 Consultant Services $17,508 Materials & Supplies $32,557 Travel $26,679 Other $17,926 Subawards/Consortium/Contractual Costs $6,899,408 Publication Costs $2,918 Federal Direct Costs $7,205,867 Federal F&A Costs $294,133 Approved Budget $7,500,000 Total Amount of Federal Funds Obligated (Federal Share) $7,500,000 TOTAL FEDERAL AWARD AMOUNT $7,500,000 AMOUNT OF THIS ACTION (FEDERAL SHARE) $7,500,000 SUMMARY TOTALS FOR ALL YEARS THIS AWARD CUMULATIVE TOTALS $7,500,000 $7,500,000
$7,500,000 $7,500,000 4 $7,500,000 $7,500,000
1 2 3
$7,500,000 $7,500,000. $7,500,000 $7,500,000
Recommended future year total cost support, subject to the availability of funds and satisfactory
progress of the project
Fiscal Information:
CFDA Name: Allergy and Infectious Diseases Research CFDA Number: 93.855 EIN: 1636005396A6
Document Number: UAI142759A PMS Account Type: P (Subaccount)
Fiscal Year: 2019 IC_| CAN 2019 2020 2021 | 2022 2023 Al_| 8472315 | $7,500,000 $7,500,000 $7,500,000 _| $7,500,000 $7,500,000
Recommended future year total cost support, subject to the availability of funds and satisfactory
progress of the project
NIH Administrative Data:
PCC: M65B B / OC: 414L / Released: |) (02/28/2019
Award Processed: 03/06/2019 12:03:47 AM
SECTION Il — PAYMENT/HOTLINE INFORMATION — 1U19AI142759-01
For payment and HHS Office of Inspector General Hotline information, see the NIH Home Page
at http//grants.nih.gov/grants/policy/awardconditions.htm
SECTION Ill - TERMS AND CONDITIONS — 1U19A1142759-01
This award is based on the application submitted to, and as approved by, NIH on the above-titled project and is subject to the terms and conditions incorporated either directly or by reference in
the following:
a. The grant program legislation and program regulation cited in this Notice of Award.
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b. Conditions on activities and expenditure of funds in other statutory requirements, such as
those included in appropriations acts.
45 CFR Part 75.
National Policy Requirements and all other requirements described in the NIH Grants
Policy Statement, including addenda in effect as of the beginning date of the budget
period.
e. Federal Award Performance Goals: As required by the periodic report in the RPPR or in the final progress report when applicable.
f. This award notice, INCLUDING THE TERMS AND CONDITIONS CITED BELOW.
a9
(See NIH Home Page at http://grants.nih.gov/grants/policy/awardconditions,htm for certain references cited above.)
Research and Development (R&D): All awards issued by the National Institutes of Health (NIH) meet the definition of “Research and Development” at 45 CFR Part§ 75.2. As such, auditees should identify NIH awards as part of the R&D cluster on the Schedule of Expenditures of Federal Awards (SEFA). The auditor should test NIH awards for compliance as instructed in Part V, Clusters of Programs. NIH recognizes that some awards may have another classification for purposes of indirect costs. The auditor is not required to report the disconnect (i,e., the award is classified as R&D for Federal Audit Requirement purposes but non-research for indirect cost rate purposes), unless the auditee is charging indirect costs at a rate other than the rate(s) specified in the award document(s).
This institution is a signatory to the Federal Demonstration Partnership (FDP) Phase VI Agreement which requires active institutional participation in new or ongoing FDP demonstrations and pilots.
Carry over of an unobligated balance into the next budget period requires Grants Management Officer prior approval.
This award is subject to the requirements of 2 CFR Part 25 for institutions to receive a Dun & Bradstreet Universal Numbering System (DUNS) number and maintain an active registration in the System for Award Management (SAM). Should a consortium/subaward be issued under this award, a DUNS requirement must be included. See http://grants.nih.gov/grants/policy/awardconditions.htm for the full NIH award term implementing this requirement and other additional information.
This award has been assigned the Federal Award Identification Number (FAIN) U19A1142759. Recipients must document the assigned FAIN on each consortium/subaward issued under this award.
Based on the project period start date of this project, this award is likely subject to the Transparency Act subaward and executive compensation reporting requirement of 2 CFR Part 170. There are conditions that may exclude this award; see http://grants.nih.gov/grants/policy/awardconditions.htm for additional award applicability information.
In accordance with P.L. 110-161, compliance with the NIH Public Access Policy is now mandatory. For more information, see NOT-OD-08-033 and the Public Access website: http://publicaccess.nih.gov/.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XI to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts with cumulative total value greater than $10,000,000 must report and maintain information in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period, The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made
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publicly available in the designated integrity and performance system (currently the Federal Awardee Performance and Integrity Information System (FAPIIS)). Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75. This term does not apply to NIH fellowships.
Treatment of Program Income:
Additional Costs
SECTION IV — Al Special Terms and Conditions —- 1U19AI142759-01
Clinical Trial Indicator: No This award does not support any NIH-defined Clinical Trials. See the NIH Grants Policy Statement Section 1.2 for NIH definition of Clinical Trial.
This Notice of Award (NoA) includes funds for activity with Southern Research Institute in the amount of $3,617,511 ($1,652,547 direct costs + $1,964,964 F&A costs).
This Notice of Award (NoA) includes funds for activity with Emory University in the amount of $372,055 ($208,434 direct costs + $163,621 F&A costs).
This Notice of Award (NoA) includes funds for activity with Vanderbilt University in the amount of $441,221 ($291,808 direct costs + $149,413 F&A costs).
This Notice of Award (NoA) includes funds for activity with University of North Carolina Chapel Hill in the amount of $841,125 ($541,929 direct costs + $299,196 F&A costs).
This Notice of Award (NoA) includes funds for activity with Oregon Health and Science University in the amount of $755,624 ($490,665 direct costs + $264,959 F&A costs).
This Notice of Award (NoA) includes funds for activity with University of Colorado at Denver in the amount of $246,958 ($163,669 direct costs + $83,289 F&A costs),
This Notice of Award (NoA) includes funds for activity with University of Texas Medical Branch in the amount of $271,207 ($171,650 direct costs + $99,557 F&A costs).
This Notice of Award (NoA) includes funds for activity with Washington University in the amount of $353,706 ($226,010 direct costs + $127,696 F&A costs).
This award is issued as a Cooperative Agreement, a financial assistance mechanism in which substantial NIH scientific and/or programmatic involvement is anticipated in the performance of the activity. This award is subject to the Terms and Conditions of Award as set forth in Section VI: Award Administrative Information of RFA Al-17-042, “Centers of Excellence for Translational Research (CETR) (U19 Clinical Trial Not Allowed),” posted date 11/30/2017, which are hereby incorporated by reference as special terms and conditions of this award.
This RFA may be accessed at: http://grants.nih.gov/grants/quide/index.html
In accordance with the NIAID Financial Management Plan, NIAID does not provide funds for inflationary increases. Committed future year (s) funding was adjusted accordingly. See: https://www.niaid.nih.gov/grants-contracts/financial-management-plan.
In addition to the PI, any absence, replacement, or substantial reduction in effort of the following individual(s) below, requires the written prior approval of the National Institutes of Health awarding component.
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sohtiee
Awardees who conduct research involving Select Agents (see 42 CFR 73 for the Select Agent list; and 7 CFR 331 and 9 CFR 121 for the relevant animal and plant pathogens
at http://www.selectagents.gov/Regulations.html) must complete registration with CDC (or APHIS, depending on the agent) before using NIH funds. No funds can be used for research involving Select Agents if the final registration certificate is denied.
Prior to conducting a restricted experiment with a Select Agent or Toxin, awardees must notify the NIAID and must request and receive approval from CDC or APHIS.
feeeed
Select Agents:
Awardee of a project that at any time involves a restricted experiment with a select agent, is responsible for notifying and receiving prior approval from the NIAID. Please be advised that changes in the use of a Select Agent will be considered a change in scope and require NIH awarding office prior approval. The approval is necessary for new select agent experiments as well as changes in on-going experiments that would require change in the biosafety plan and/or biosafety containment level. An approval to conduct a restricted experiment granted to an individual cannot be assumed an approval to other individuals who conduct the same restricted experiment as defined in the Select Agents Regulation 42 CFR Part 73, Section 13.b (http://www.selectagents.gov/Requlations.html).
Highly Pathogenic Agent:
NIAID defines a Highly Pathogenic Agent as an infectious Agent or Toxin that may warrant a biocontainment safety level of BSL3 or higher according to the current edition of the CDC/NIH Biosafety in Microbiological and Biomedical Laboratories (BMBL) (http://www.cde.gov/OD/ohs/biosfty/bmbI5/bmb|5toc.htm). Research funded under this grant must adhere to the BMBL, including using the BMBL-recommended biocontainment level at a minimum. If your Institutional Biosafety Committee (or equivalent body) or designated institutional biosafety official recommend a higher biocontainment level, the highest recommended containment level must be used.
When submitting future Progress Reports indicate at the beginning of the report:
Ifno research with a Highly Pathogenic Agent or Select Agent has been performed or is planned to be performed under this grant.
If your IBC or equivalent body or official has determined, for example, by conducting a risk assessment, that the work being planned or performed under this grant may be conducted ata biocontainment safety level that is lower than BSL3.
If the work involves Select Agents and/or Highly Pathogenic Agents, also address the following points:
Any changes in the use of the Agent(s) or Toxin(s) including its restricted experiments that have resulted in a change in the required biocontainment level, and any resultant change in location, if applicable, as determined by your |BC or equivalent body or official.
If work with a new or additional Agent(s)/Toxin(s) is proposed in the upcoming project period, provide:
0 Alist of the new and/or additional Agent(s) that will be studied;
o A description of the work that will be done with the Agent(s), and whether or not the work is a restricted experiment;
©. The title and location for each biocontainment resource/facility, including the name of the organization that operates the facility, and the biocontainment level at which the work will be conducted, with documentation of approval by your IBC or equivalent body or official. It is important to note if the work is being done in a new location.
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The budget period anniversary start date for future year(s) will be March 1.
STAFF CONTACTS
The Grants Management Specialist is responsible for the negotiation, award and administration of this project and for interpretation of Grants Administration policies and provisions. The Program Official is responsible for the scientific, programmatic and technical aspects of this project. These individuals work together in overall project administration. Prior approval requests (signed by an Authorized Organizational Representative) should be submitted in writing to the Grants Management Specialist, Requests may be made via e-mail
Grants Management Specialist: Roberta D Wolcott Email: wolcottr@niaid.nih.gov Phone: 240-669-2964 Fax: 301-493-0597
Program Official: Maureen J. Beanan
Email: beananm@mail.nih.gov Phone: 240-292-0999 SPREADSHEET SUMMARY
GRANT NUMBER: 1U19AI142759-01
INSTITUTION: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Budget Year 1 Year2 Year 3 Year 4 Year 5 Salaries and Wages $158,059 146,399 | $147,124 147,549 146,934 Fringe Benefits $50,812 146,639 $46,871 $47,006 $46,810 Personnel Costs (Subtotal) $208,871 193,038 | $193,995 194,555 193,744 Consultant Services $17,508 17,626 $17,714 17,765 $17,691 Materials & Supplies $32,557 14,060 $14,129 14,169 $14,111 Travel $26,679 126,859 $26,993 $27,070 26,957 Other $17,926 18,046 $18,136 18,188 $18,113 Subawards/Consortium/Contract | $6,899,40 7,094,61 | $7,092,60 | $7,091.43 | $7,093,13 ual Costs 8 4 4 oO 4 Publication Costs $2,918 3,358 $3,374 13,384 $3,370 TOTAL FEDERAL DC $7,205,86 '7,367,60 | $7,366,94 | $7,366.56 | $7,367,11 7 4 5 fl 7 TOTAL FEDERAL F&A $294,133 132,399 | $133,055 133,439 | $132,883 TOTAL COST $7,500,00 7 500,00 | $7,500,00 | $7,500.00 | $7,500,00 i?) 0 i} 0 0 Facilities and Administrative Costs__| Year 1 Year 2 Year 3 Year 4 Year 5 F&A Cost Rate 1 48.5% 48.5% 48.5% 48.5% 48.5% F&A Cost Base 1 $606,459 | $272,987 | $274,341 | $275,131 | $273,986 F&A Costs 1 $294,133 | $132,399 | $133,055 | $133,439 | $132,883
NIHPa@@G007
Pl: WHITLEY, RICHARD J.
Title: Antiviral Drug Discovery and Development Center (AD3C)
Received: 03/29/2018
FOA: Al17-042 Clinical Trial:Not Allowed
Council: 01/2019
Competition ID: FORMS-E
FOA Title: Centers of Excellence for Translational Research (CETR) (U19 Clinical Trial Not
Allowed)
1: U19 Al142759-01
Dual:
Accession Number: 4155813.
IPF: 1288803 Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Former Number: Department:
IRG/SRG: ZAI1 LG-M (J2) | AIDS: N Expedited: N Subtotal Direct Costs Animals: Y New Investigator: (excludes consortium F&A) | Humans: N Early Stage Investigator: Year1: 4,865,430 Clinical Trial: N
Year 2: 4,894,865 Current HS Code: 10
Year3: 4,897,002 HESC: N
Year4: 4,914,416
Year5: 4,934,134
Senior/Key Personnel: Organization: Role Category: RICHARD WHITLEY University of Alabama at Birmingham PD/PI
Additions for Review
Supplemental Material
Post-submission materials
of the applications
NIH - 000008
Reviewers please consider the post-submission materials in your evaluation
APPLICATION FOR FEDERAL ASSISTANCE SF 424 (R&R)
OMB Number: 4040-0001 Expiration Date: 1031/2019
3. DATE RECEIVED BY STATE | State Application Identifier
1. TYPE OF SUBMISSION*
4.a. Federal Identifier
@ Application O Changed/Corrected
Application
O Pre-application
b. Agency Routing Number
2. DATE SUBMITTED 5. APPLICANT INFORMATION
Application Iden
Legal Name*: UNIVERSITY OF ALABAMA AT BIRMINGHAM Department:
Division:
Street1*: UNIVERSITY OF ALABAMA AT BIRMINGHAM Street2: 1720 2nd Ave South, AB1170
City*: BIRMINGHAM
County:
State": AL: Alabama
Province:
Country*: USA: UNITED STATES
ZIP / Postal Code*: 352940111
Person to be contacted on matters involving this application
Prefix: Mr. First Name": @@asene Middle Name: Position/Title:
Street1*: 1720 2nd Avenue South, AB1170
Street2:
City’: Birmingham
County:
State": AL: Alabama
Province:
Country": USA: UNITED STATES
ZIP/Postal Code*: = 352940111 Phone Number": | (6) (G)(A),()
6. EMPLOYER IDENTIFICATION NUMBER (EIN) or (TIN) 7. TYPE OF APPLICANT*
Fax Number:
OOM.
c. Previous Grants.gov Tracking Number Organizational DUNS*: 0636907050000
Last Name": maere Suffix:
Email OOAWO 1636005396A6
H: Public/State Controlled Institution of Higher Education
Other (Specify): Small Business Organization Type
O Women Owned
O Socially and Economically Disadvantaged
8. TYPE OF APPLICATION* @ New O Resubmission
O Renewal O Continuation O Revision
If Revision, mark appropriate box(es). OA Increase Award OD. Decrease Duration O E. Other (specify) :
OB. Decrease Award OC. Increase Duration
Is this application being submitted to other agencies?* Des
@No What other Agencies?
9. NAME OF FEDERAL AGENCY* National Institutes of Health
10. CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER TITLE:
11. DESCRIPTIVE TITLE OF APPLICANT'S PROJECT* Antiviral Drug Discovery and Development Center (AD3C)
12. PROPOSED PROJECT Start Date* 03/01/2019
Ending Date" 02/29/2024
13. CONGRESSIONAL DISTRICTS OF APPLICANT AL-007
Tracking Number: GRANT12598083
NIH - 000099 ;
Funding Opportunity Number: RFA-AI-17-042 . Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
SF 424 (R&R) APPLICATION FOR FEDERAL ASSISTANCE Page 2
14. PROJECT DIRECTOR/PRINCIPAL INVESTIGATOR CONTACT INFORMATION
Prefix: First Name": RICHARD Middle Name: J. Last Name*: WHITLEY Suffix: Position/Title: Distinguished Professor Organization Name*: University of Alabama at Birmingham Department: Division: Streett*: HOA.OO Street2: City*: Birmingham County: State": AL: Alabama Province: Country": USA: UNITED STATES ZIP/Postal Code*: 352330000 Phone Number*: 205-934-5316 Fax Number: 205-934-8559 Email": rwhitley@peds.uab.edu 15. ESTIMATED PROJECT FUNDING 16.IS APPLICATION SUBJECT TO REVIEW BY STATE EXECUTIVE ORDER 12372 PROCESS?* a. YES THIS PREAPPLICATION/APPLICATION WAS MADE a. Total Federal Funds Requested’ $45,087,198.00 © AVAILABLE TO THE STATE EXECUTIVE ORDER 12372 b. Total Non-Federal Funds” $0.00 PROCESS FOR REVIEW ON: c. Total Federal & Non-Federal Funds* $45,087,198.00] DATE: d. Estimated Programiincome” $0.00|1,. NO @ PROGRAM IS NOT COVERED BY E.0. 12372; OR © PROGRAM HAS NOT BEEN SELECTED BY STATE FOR REVIEW
17. By signing this application, | certify (1) to the statements contained in the list of certifications” and (2) that the statements herein are true, complete and accurate to the best of my knowledge. | also provide the required assurances * and agree to comply with any resulting terms if | accept an award. | am aware that any false, fictitious, or fraudulent statements or claims may subject me to criminal, civil, or administrative penalties. (U.S. Code, Title 18, Section 1001)
@ | agree* * The ist of cerifications and assurances, or an Intemet site where you may obtain this it. is contained in the announcement or agency speotic nstnuctions 18. SFLLL or OTHER EXPLANATORY DOCUMENTATION File Name: 19. AUTHORIZED REPRESENTATIVE Prefix: First Name’: Pane Middle Name: Last Name*: #@ame Suffix: Positior/Title*: ©) GB) A), ©) ©) Organization Name*: University of Alabama at Birmingham Department: Office of Sponsored Programs Division: Street1*: 1720 2nd Avenue South AB1170 Street2: City*: Birmingham County: State*: AL: Alabama Province: Country*: USA: UNITED STATES ZIP/Postal Code": 352940111 Phone Number* <6) G) (A). 6) © Fax Number: 205-975-5977 Email": OOA OO Signature of Authorized Representative’ Date Signed* OOA.0OO 03/29/2018
20. PRE-APPLICATION — File Name:LO|_Whitley RFA-Al-17-042_SENT_2.8.18.pdf 21. COVER LETTER ATTACHMENT File Name:AD3C_Cover_Letter_3.26.18.pdf
: 4 Funding Opportunity Number: RFA-Al-17-042 . Received Date: RECTUM Oer can lee Seoee NIH - 00004Qe 2 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
SY. =} SCHOOL OF MEDICINE
Department of Pediatrics
February 7, 2018
Lianyong Gao, Ph.D. National Institute of Allergy and Infectious Diseases (NIAID) Mail to: gaol2@niaid.nih.gov
RE: RFA-Al-17-042: Centers of Excellence for Translational Research Letter of Intent
Dear Dr. Gao:
Please allow this letter to stand as our Letter of Intent for submission of an application in response to the aforementioned RFA. The title of the application will be Antiviral Drug Development and Discovery Center (AD3C). | will serve as the Principal Investigator/Project Director for the entire application; however, each of the components of the application will have its own Principal Investigator as listed below. We have identified other Key Personnel according to each of the research proposals.
Project 1 - Flaviviruses
Principal Investigator —
Name: Pei-Yong Shi, Ph.D.
Title: |.H. Kempner Professor of Human Genetics, Department of Biochemistry & Molecular Biology,
Address: University of Texas Medical Branch, Galveston, Texas 77555
Telephone: 409-772-6370
Other Key Personnel — 1) ®@@:6©, M.D., Ph.D., Washington University School of Medicine, St. Louis,
MO 2)/(@@A5OOPh_D., Oregon Health and Science University, Portland, OR 3) Ph.D., Oregon Health and Science University, Portland, OR
Project 2 - Coronaviruses Principal Investi. -
Name: Mark R. Denison, M.D.
Title: Craig Weaver Professor of Peciatrics, Interim Director Division of Infectious Diseases, Professor of Pathology, Microbiology and Immunology
Address: Vanderbilt University School of Medicine®®® MCN, 1161 21S' Avenue South, Nashville, TN 37232
Telephone: 615-322-2250
Division of Infectious Diseases. | The University of Clinical Virology | Alabama at Birmingham 303 Children’s Herbor Building | Mailing Address: 1600 6th Avenue South CHB 303 205.934.5316 1600 7TH AVE S
Fax 205.93 4\ BARR _ ob tH eS 3 AL 35233-1711
Pro-application Attachment
Contact PD/PI: WHITLEY, RICHARD J.
Other Key Personnel —
1) (OCS), Ph.D. University of North Carolina at Chapel Hill 2) ®@W.0© Ph.D. University of North Carolina at Chapel Hill
Project 3 - Alphaviruses
Principal Investigator —
Name: Daniel Streblow, Ph.D.
Title: Associate Scientist, Vaccine and Gene Therapy Institute, Research Assistant Professor, Department of Molecular Microbiology and Immunology
Address: Oregon Health and Science University, Portland, OR
Telephone: 503-418-2705
Other Key Personnel —
1) ®)G)@VOG;, Ph.D., Oregon Health and Science University 2) | ©@)@.©@, Ph.D., University of North Carolina at Chapel Hill 3) ®OAMWO, Ph.D. University of Colorado at Denver
Project 4 — Influenza
Principal Investigator —
Name: Mark N. Prichard, Ph.D.
Title: Professor
Address: University of Alabama at Birmingham @@YAXOO 1600 6" Ave. South
Birmingham, AL 35233
Telephone: 205-934-1990
Other Key Personnel —
1) | ®@AOO Southern Research 2) Richard Whitley, UAB
Core A - Administrative
Principal Investigator
Name: Richard J. Whitley, M.D.
Title: Distinguished Professor
Address: University of Alabama at Birmingham ©9@© 41600 6" Avenue South
Birmingham, AL 35233
Telephone: 205-934-5316
NIH - 0000420 4
Pro-application Attachment
Contact PD/PI: WHITLEY, RICHARD J.
Other Key Personnel —
1) UAB 2) UAB Core B - Assay Core
Principal Investigator
Name: J. Robert Bostwick, Ph.D. Title: Director, High Throughput Screening Center Address: Southern Research
Birmingham, AL 35205 Telephone: 205-581-2000
Core C - Medicinal Chemistry Core
Principal Investigator
Name: Ashish K. Pathak, Ph.D., Title: Vice-President, Drug Discovery Division Address: Southern Research
, Birmingham, AL 35205 Telephone: 205-581-2000
Other Key Personnel —
1) , Ph.D., Southern Research
, Ph.D., Southern Research
, PhD, Emory Institute for Drug Disovery
, PhD, Emory Institute for Drug Disovery
If | can provide further information, | would be happy to do so.
Richard J. .D. Distinguished Professor Loeb Scholar Chair in Pediatrics
Professor of Pediatrics, Microbiology, Medicine and Neurosurgery E-Mail Address: rwhitley@peds.uab.edu
Phone Number: 205-934-5316
NIH - 00004 3,6 5
Pro-application Attachment
424 R&R and PHS-398 Specific Table Of Contents
SF 424 R&R Cover Page. Table of Content: Summaries.......
Component Summary. Performance Sites Summar. Human Subjects - Clinical Study Summary. Composite App! Component Budget ‘Summavy. Categories Budget Summary. Senior/Key personnel Summary.
Biosketches.... Performance Sites. Research & Related Other Project Information.
Project Summary/Abstract(Description
Project Narrative...
Facilities & Other Resources. Research & Related Senior/Key Person. PHS398 Cover Page Supplement. PHS 398 Research Pla
Specific Aims.....
Research Strategy.
PHS Human Subjects and Cl
Vertebrate Animals.
Bibliography & Ref
Consortium/Contractual Arrange:
Letters of Support.....
Resource Sharing Plat Admin-Core. Admin-Core-0 Performance Sites.... Research & Related Other Project Information.
Project Summary/Abstract(Description
Facilities & Other Resources.......... Research & Related Senior/Key Person. Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification...
Research & Related Cumulative Budget
PHS398 Cover Page Supplement.
PHS 398 Research Pla
ical Trials Informa’
Resource Sharing Plants Core... Core-001. (118) Performance Sites..... Research & Related Other Project Project Summary/Abstract(Description Facilities & Other Resources. Equipment........ Research & Related Senior/Key Person. Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification.
NIH - 00008 4,6 ¢
Research & Related Cumulative Budge’
PHS398 Cover Page Supplement.
PHS 398 Research Pla Specific Aims... Research Strate:
Select Agent Research....... Bibliography & References Cite Resource Sharing Plan(s)... Authentication of Key Biological and/or Chemical Resources. Core-002 (572) - Medicinal Chemistry and Lead Development Core - SR. Performance Sites..... Research & Related Other Project Information. Project Summary/Abstract(Description Facilities & Other Resources. Equipment....... Research & Related Senior/Key Person. Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification... Research & Related Cumulative Budg! PHS398 Cover Page Supplement. PHS 398 Research Plan. Specific Aims.. Research Strateg) PHS Human Subjects and Clinical Trials Information. Vertebrate Animals....... Bibliography & References Cited. Consortium/Contractual Arrangements. Resource Sharing Plan(s)..... Authentication of Key Biolog Core-003 (717) - Medicinal Chemistry and Lead Development Core - EIDD. Performance Sites.... Research & Related Other Project Information. Project Summary/Abstract(Description Facilities & Other Resources.
y Research & Related Budget Year - 1 Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification... Research & Related Cumulative Budge’ PHS398 Cover Page Supplement. PHS 398 Research Pla Specific Aims... Research Strategy. PHS Human Subjects and Clinical Trials Information. Vertebrate Animals....... Consortium/Contractual Arrangements. Resource Sharing Plan(s' Project. Project- Performance Sites. Research & Relate Project Summary/Abstract( Description) Facilities & Other Resources. Equipment...... Other Attachments.
NIH - 00004 5,6 7
Product_Development_Strategy. Research & Related Senior/Key Pers: Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification....
Research & Related Cumulative Budge’
Research & Related Budget - Consortium Budget (Subaward 1
Research & Related Budget - Consortium Budget (Subaward 2)
PHS398 Cover Page Supplement.
PHS 398 Research Pla Specific Aims..... Research Strategy. PHS Human Subjects and Cl Vertebrate Animals.. Select Agent Research. Multiple PD/PI Leadership Plan. Bibliography & References Ci Letters of Support. Resource Sharing Authentication of Key Biolog!
Project-002 (506) - Project 2 - Novel Therapeutics for Emerging
Performance Sites....
Research & Related Other Project Project Summary/Abstract(Description Facilities & Other Resources. Equipmernt....... Other Attachments.
Product_Developme: Research & Related Senior/Key Person. Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Budget Justification. Research & Related Research & Related Budget - Consorti ig! Research & Related Budget - Consortium Budget (Subaward 2) Research & Related Budget - Consortium Budget (Subaward 3) PHS398 Cover Page Supplement. PHS 398 Research Plan.
Specific Aims... Research Strate: PHS Human Subjects and Clinical Trials Information. Vertebrate Animals....... Bibliography & References Cited. Resource Sharing Plan(s).. Authentication of Key Biological and/or Che:
Project-003 (100) - Project 3 - Flavivirus - UTMB.
Performance Sites....
Research & Related Other Project Information. Project Summary/Abstract(Description Facilities & Other Resources. Other Attachments.
Product_Develop! i Research & Related Seni: ey Pers Research & Related Budget Year - 1 Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year - Research & Related Budget Year -
NIH - 00008 f,6 g
Budget Justification.. Research & Related Research & Related Budget - Consortiu Research & Related Budget - Consortium Budget (Subaward 2) Research & Related Budget - Consortium Budget (Subaward 3) PHS398 Cover Page Supplement. PHS 398 Research Plan.
Specific Aims..
Bibliography & References Cited.
Resource Sharing Plan(s)..... Authentication of Key Biological and/or Che:
Project-004 (267) - Project 4 - Influenza - UAB
Performance Sites....
Research & Related Other Project Information. Project Summary/Abstract(Description, Facilities & Other Resources. Equipment. Other Attac!
Product_Develop: gy.
Research & Related Senior/Key Pers
Research & Related Budget Year - 1
Research & Related Budget Year -
Research & Related Budget Year -
Research & Related Budget Year -
Research & Related Budget Year -
Budget Justification.....
Research & Related Cumulative Budge’
Research & Related Budget - Consortium Budget (Subaward 1
PHS398 Cover Page Supplement.
PHS 398 Research Pla Specific Aims..... Research Strategy. PHS Human Subjects and Clinical Trials Information. Vertebrate Animals... Select Agent Research. Bibliography & Refere Resource Sharing Plan(s' Authentication of Key Bi
| Resources.
NIH - 00008 Tye 9
Contact PD/PI: WHITLEY, RICHARD J.
Tracking Number: GRANT12598083
2018-03-29T 16:30:43.000-04:00
Funding Opportunity Number: RFA-Al-17-042.
Overall Antiviral Drug Discovery and UNIVERSITY OF ALABAMA AT WHITLEY, RICHARD J. Development Center (ADSC) BIRMINGHAM Admin-Core-001 (040) Administrative Core UNIVERSITY OF ALABAMA AT WHITLEY, RICHARD J. | BIRMINGHAM Core-001 (118) ‘Assay Core Southem Research Institute Bostwick, James R Core-002 (572) Medicinal Chemistry and Lead | Souther Research Institute Pathak, Ashish K Development Core - S2 Core-003 (717) Medicinal Chemistry and Lead Emory University — &) GB) (A).6) © Development Core - EDD Project-001 (841) Project 1 - Coronavirus UNIVERSITY OF ALABAMA AT Denison, Mark R BIRMINGHAM Project-002 (508) Project 2- Novel Therapeutics for | UNIVERSITY OF ALABAMA AT Streblow, Daniel N. Emerging Alphavirus BIRMINGHAM Project-003 (100) Project 3 - Flavivirus - UTMB UNIVERSITY OF ALABAMA AT SHI, PEI-YONG BIRMINGHAM Project-004 (267) Project 4 - Influenza - UAB | UNIVERSITY OF ALABAMA AT WHITLEY, RICHARD J. BIRMINGHAM NIH - 000!
Received Date:
Contact PD/PI: WHITLEY, RICHARD J.
Project/Performance Site Location(s) Summary
UNIVERSITY OF ALABAMA AT BIRMINGHAM OAL
UNITED STATES BIRMINGHAM Emory University, Yerkes Atlanta GA UNITED STATES —_Core-003 (717) National Primate Research Center Oregon Health & Science Beaverton OR UNITED STATES Project-002 (506) University Oregon Health & Science Portland OR UNITED STATES. Project-002 (506) University Oregon Health and Science Portland OR UNITED STATES Project-003 (100) University Southern Research Institute Birmingham AL UNITED STATES Core-001 (118) Southern Research Institute Birmingham AL UNITED STATES —Core-002 (572) Southern Research Institute Birmingham AL UNITED STATES _Project-004 (267) the University of Alabama at Birmingham AL UNITED STATES __Project-002 (506) Birmingham The University of North Carolina | Chapel Hill NC UNITED STATES _Project-001 (841) at Chapel Hill the University of North Carolina | Chapel Hill NC UNITED STATES. Project-002 (506) at Chapel Hill The University of Texas Medical | Galveston ™ UNITED STATES: Project-003 (100) Branch at Galvston UNIVERSITY OF ALABAMA AT BIRMINGHAM AL UNITED STATES — Admin-Core-001 (040) BIRMINGHAM UNIVERSITY OF ALABAMA AT | BIRMINGHAM AL UNITED STATES. Overall BIRMINGHAM UNIVERSITY OF ALABAMA AT | BIRMINGHAM AL UNITED STATES Project-001 (841) BIRMINGHAM UNIVERSITY OF ALABAMA AT BIRMINGHAM AL UNITED STATES Project-003 (100) BIRMINGHAM UNIVERSITY OF ALABAMA AT BIRMINGHAM AL UNITED STATES. Project-004 (267) BIRMINGHAM
NIH - 0000426 44
racking Number: GRANT12598083 Funding Opportunity Number: RFA-AI-17-042. Received Date: 2a 03-29T16:30:43.000-04:00 “g ay
Contact PD/PI: WHITLEY, RICHARD J.
University of Colorado Denver
Aurora | co UNITED STATES Project-002 (506) Vanderbilt University Medical Nashville TN UNITED STATES Project-001 (841) Center Washington University St.Louis | MoO UNITED STATES _| Project-003 (100) NIH - 000
Tracking Number: GRANT 12598083
2018-03-29T16:30:43.000-04:00
Funding Opportunity Number: RF/
je 12 -Al-17-042, Received Date:
Contact PD/PI: WHITLEY, RICHARD J.
Human Subjects Clinical Trials Vertebrate Animals HESC ‘Summary Overall N N M N Admin-Core-001 (040) N N N N Core-001 (118) N N N N Core-002 (572) N N ¥ N Core-003 (717) N N ¥ N Project-001 (841) N N Y N Project-002 (506) N N bg N Project-003 (100) N N Y N Project-004 (267) N N ¥ N
NIH - 0000246 13
Tracking Number: GRANT12598083. Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00 “e ay
Contact PD/PI: WHITLEY, RICHARD J.
Study Summary
NIH - 000022, 14
Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-A!-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Composite Application Budget Summary
Salary, Wages and Fringe Benefits
Equipment 0 i) O) 0 Travel 32,000 32,000 32,000 | 32,000 Participant/Trainee Support Costs ii t) oO oO. ° Other Direct Costs (excluding Consortium) 85,050 63,250 63,250 63,250 Consortium Costs 8,270,815 8,518,192 8,520,802 8,543,545, Direct Costs 8,638,388 8,843,427 8,846,037 8,868,780 Indirect Costs 157,739
Total Direct Costs less Consortium F&A
NIH policy (NOT-OD-05-004) allows applicants to exciude consortium/contractual F&A costs when determining if an application falls at or beneath any applicable direct cost limit. When a direct cost limit is specified in an FOA, the following table can be used to determine if your application falls within that limit.
Total Direct Costs less Consortium F&A 4,865,430 4,894,865 4,897,002 4,914,416 4,934,134
“This application includes at least one component led by an organization that has a DUNS different than the Applicant Organization. The indirect cost calculation for the applicant organization ma not include all allowed Indirect Costs for the first $25K of requested consortium costs and, therefore, may appear less than expected. No action is required from the applicant; NIH will make any appropriate corrections to the budget calculations administratively. The application review will not be affected.
NIH - 0000226 15 Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
‘Component Budget Summary
Salary, Wages and Fringe Benefits 103,721
Equipment
Travel
Participant/Trainee Support Costs
Other Direct Costs (excluding Consortium)
Consortium Costs
Direct Costs 171,221 171,221
Indirect Costs 119,417 83,042
Salary, Wages and Fringe Benetits
Equipment
Travel
Participant/Trainee Support Costs oO
Other Direct Costs (excluding 364,120 Consortium) |
Consortium Costs oO
Direct Costs 674,467
Indirect Costs 605,495
Salary, Wages and Fringe Beneiits
NIH - 000024, 16 Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Equipment
Travel
5,238
Participant/Trainee Support Costs
0
Other Direct Costs (excluding Consortium)
214,623
239,747
239,747
Consortium Costs
o
oO
o
Direct Costs
1,019,532 1,127,160
1,127,160
1,127,160 1,127,160
Indirect Costs
Salary, Wages and Fringe Benetits
Equipment
1,415,787
1,562,349
178,680
1,562,349
1,562,349 1,562,349
Travel
Participant/Trainee Support Costs.
Other Direct Costs (excluding Consortium)
Consortium Costs
Direct Costs
Indirect Costs
Salary, Wages and Fringe Benefits
Equipment
Travel
Participant/Trainee Support Costs
Other Direct Costs (excluding Consortium)
Tracking Number: GRANT12598083
NIH - 000!
OZ Re 17 Funding Opportunity Number: RFA-Al-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Consortium Costs
1,245,724
Direct Costs
1,245,724
Indirect Costs
Salary, Wages and Fringe Benefits
Equipment
0
Travel
Participant/Trainee Support Costs.
Other Direct Costs (excluding Consortium)
Consortium Costs
1,225,790
1,225,475
1,225,687
Direct Costs
1,225,790
1,225,475,
1,225,687
Indirect Costs
Salary, Wages and Fringe Benetits
ti)
i)
0
Equipment
Travel
Participant/Trainee Support Costs
Other Direct Costs (excluding Consortium)
Consortium Costs.
1,035,067
Direct Costs
1,035,067
Indirect Costs
Salary, Wages and Fringe Beneiits
36,375
126,264
Tracking Number: GRANT12598083
NIH - 000!
Funding Opportunity Number: RFA-Al-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Equipment
Travel
Participant/Trainee Support Costs
Other Direct Costs (excluding Consortium)
24,750
Consortium Costs
623,628
819,681
Direct Costs
819,980
973,895
Indirect Costs
Tracking Number: GRANT12598083
107,356
74,697
NIH - 00002%40 19 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Categories Budget Summary
76,370
Core-001 (118) 86,071
Core-002 (572) | 94,881
Core-003 (717) 5,275
Project-001 (841) 0
Project-002 (506) 0
Project-003 (100) 0
Project-004 (267) 78,371 78,371 78,371
27,351 27,351 27,351
Core-001 (118) 224,276 176,347 176,347
Core-002 (572) 716,723, 787,204 787,204
Core-0083 (717) 179,072 189,974
Project-001 (841) 0 0
Project-002 (506)
Project-003 (100)
Project-004 (267)
NIH - 000028. 20 Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
103,721
Core-001 (118) 310,347
Core-002 (572) 799,671
Core-003 (717) 178,680
Project-001 (841) °
Project-002 (506)
Project-003 (100)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100) Project-004 (267)
NIH - 000028, 24 Tracking Number: GRANT12598083, Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Tracking Number: GRANT12598083
NIH - 000 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (672)
Core-003 (717)
Tracking Number: GRANT12598083
NIH - 00003440 23 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Tracking Number: GRANT12598083
NIH - 000032,6 24 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Tracking Number: GRANT12598083
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
180,427
139,843.
139,843
139,843
Core-002 (572)
182,568
197,218
197,218
197,218
Core-003 (717)
Project-001 (841)
53,020
0
47,656
42,136
oO
36,451
i)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (672)
Core-003 (717)
NIH - 000033,, 95
Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Tracking Number: GRANT12598083
NIH - 000034,6 26 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Tracking Number: GRANT12598083
(040)
Core-001 (118)
Core-002 (572)
0
0
Core-003 (717)
0
0
Project-001 (841)
1,248,560
1,250,887
Project-002 (506)
1,225,790
1,225,687
Project-003 (100)
1,040,903
1,051,820
807,669
819,881
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
NIH - 000038,, 97
Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
Tracking Number: GRANT12598083
NIH - 000038 )0 2 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Admin-Core-001 (040)
Core-001 (118)
Core-002 (572)
Core-003 (717)
Project-001 (841)
Project-002 (506)
Project-003 (100)
Project-004 (267)
38,500
Admin-Core-001 38,500 38,500 38,500 (040) |
T Core-001 (118) 364,120 288,920 288,920 288,920
Core-002 (572)
214,623
299,747
Core-003 (717)
Project-001 (841)
1,227,383
71,320 65,956
1,245,724
94,751 48,891
1,250,887
Project-002 (506)
1,223,206 _
1,225,475,
1,225,687
Project-003 (100)
1,035,067
1,040,903
1,046,664
1,051,820
Project-004 (267)
Admin-Core-001 (040)
171,221
670,178 | 832,419
171,221
832,419
171,221
844,631
171,221
Core-001 (118) 674,467, 551,338 551,338 551,338 Core-002 (572) 1,019,532, 1,127,160 1,127,160 1,127,160 Core-003 (717) 250,000 250,000 250,000 250,000
Tracking Number: GRANT12598083
NIH - 00003%6 29 Funding Opportunity Number: RFA-AI-17-042.
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Tracking Number: GRANT12598083
Project-001 (841)
1,227,383
1,245,724
Project-002 (506)
1,223,206
1,225,475.
Project-003 (100)
1,035,067
1,046,664
Project-004 (267)
Admin-Core-001 (040)
819,980
119,417
961,683
Core-001 (118)
605,495
Core-002 (572)
1,415,787
Core-003 (717)
Project-001 (841)
196,250
24,250
Project-002 (506)
36,375
Project-003 (100)
36,375
0
Project-004 (267)
Admin-Core-001 (040)
107,356
290,638
74,697
74,697
254,263
Core-001 (118)
1,279,962
1,059,511
1,059,511
Core-002 (572)
2,435,319
2,689,509
2,689,509
Core-003 (717)
446,250
446,250
446,250
Project-001 (841)
1,251,633
1,245,724
1,250,887
1,248,255
Project-002 (506)
1,259,581
1,225,475
1,225,687
1,226,109
Project-003 (100)
1,071,442
1,046,664
1,051,820
1,141,185
Project-004 (267)
927,336
NIH - 000038. 30 Funding Opportunity Number: RFA-Al-17-042.
1,036,380
1,048,592
1,028,494
Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
Senior/Key Personnel ‘Summary
WHITLEY, RICHARD J. University of Alabama at PD/PI(Contact) Overall Birmingham Southern Research Other: Core Co-Lead Core-002 (572) The University of North Carolina Co-Investigator Project-001 (841) at Chapel Hill Southern Research Other: Core Lead Core-001 (118) ‘Southern Research Other: Project Go-lead Project-004 (207) Vanderbilt University Medical Faculty Project-001 (841) Center Oregon Health & Science Co-Investigator Project-002 (506) University Vanderbilt University Medical Other: Project Lead Project-001 (841) Center Washington University Co-Investigator Project-003 (100)
University of Alabama at Birmingham
Other: Core Associate
Admin-Core-001 (040)
The University of North Carolina Co-Investigator Project-001 (841) ‘at Chapel Hill The University of North Carolina Co-Investigator Project-002 (506) at Chapel Hill Oregon Health & Science Co-Investigator Project-003 (100) Unversity Gilead Sciences, Inc Consultant Project-001 (841) University of Colorado Denver Co-Investigator Project-002 (506) Oregon Health & Science Co-Investigator Project-003 (100) University Emory University Other: Subcontract PI Core-003 (717) Pathak, Ashish K Southern Research Other: Core Lead Core-002 (572) PRICHARD, MARK Neal University of Alabama at Co-Investigator Project-004 (287) Birmingham Vanderbilt University Medical Faculty Project-001 (841) ‘Center Southern Research Other: Lab Supervisor Core-001 (118) The University of North Carolina Co-Investigator Project-001 (841) at Chapel Hill NIH - 000! 31 Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-AI-17-042. Received Date:
2018-03-29T 16:30:
.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
SHI, PEIL-YONG The University of Texas Medical Other: Project Lead Project-003 (100) Branch at Galvesten The University of North Carolina Co-Investigator Project-001 (841) at Chapel Hill Streblow, Danie! N. Oregon Health & Science Other: Project Lead Project-002 (506) University uthern Research Other: Core Co-Lead Cora-002 (572) University of North Carolina | Co-Investigator Project-001 (841) Chapel Hill uthern Research Other: Senior Project Manager —_Project-004 (267)
WHITLEY, RICHARD J. University of Alabama at Other: Core Lead Admin-Core-001 (040)
Birmingham WHITLEY, RICHARD J. University of Alabama at Other: Project Lead Project-004 (267) Birmingham The University of North Carolina Other: Research Associate Project-001 (841) al Chapel Hill NIH - 000! Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-AI-17-042. Received Date:
2018-03-29T 16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: Richard James Whitley, M.D.
eRA COMMONS USER NAME (credential, e.g., agency login); Xt
POSITION TITLE: UAB Distinguished Professor of Pediatrics, Microbiology, Medicine & Neurosurgery, Loeb Eminent Scholar Chair in Pediatrics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION freer niei bee FIELD OF STUDY Duke University, Durham, NC B.A. 05/1967 Chemistry George Washington University, Washington DC M.D. 05/1971 Medicine The University of Alabama at Birmingham, AL Intern/Res. 06/1973 | Pediatrics The University of Alabama at Birmingham, AL Fellowship 06/1976 | Infectious Diseases and Virology
A. Personal Statement
| have spent 35 years developing antiviral drugs from lead molecules through all phases of clinical development (Phase | to III). This work has led to several NDAs for multiple drugs and a variety of diseases. | am responsible for the NIH-Funded Antiviral Drug Discovery and Development Center. The purpose of the center is to discover potential new drugs which could be used to treat infections such as West Nile virus and influenza that routinely infect US citizens, and for which we have limited or no treatments. We will also strive to develop therapies for emerging infections such as coronaviruses, dengue and chikungunya which pose risks for traveling US citizens or could be imported into the country by others. | have worked with and mentored pre- and post-doctoral fellows and assisted them through all phases of their professional development.
B. Positions and Honors
Positions and Employment
Present-Distinguished Professor at UAB; Loeb Eminent Scholar Chair in Pediatrics; Professor of Pediatrics, Microbiology, Medicine, & Neurosurgery; Scientist, Cancer Research and Training Center; Senior Leader, Associate Director for Drug Discovery and Development, Comprehensive Cancer Center, University of Alabama at Birmingham Senior Scientist, Department of Gene Therapy; Co-Founder and Co-Director Alabama Drug Discovery Alliance; Vice-Chairman Department of Pediatrics; Director Pediatric Infectious Diseases. Honors
Award of Commendation, University of Alabama (1977); Assoc Editor: Journal of Infectious Diseases (2005- Present). President: Inter. Society for Antiviral Research (1988-1990);Canon Eley Lecturer, Harvard (1991); Netter Professor (1992); Schneierson Professor (1992); MacLaughlin Professor (1992); Distinguished Faculty Lecturer, UAB (1998); John Enders Lecturer, IDSA (2000); Aventis Award, ASM (2000); John Soothill Lecture (2001); Elion Award, International Society for Antiviral Research (2004); UAB President's Medal (2007), Past President and Council Member IDSA (2008-13), Inaugural Distinguished Clinical Research Scholar/Educator in Residence at the NIH Clinical Center (2013). Elected Member: Society of Pediatric Research, American Pediatric Society, American Society of Clinical Investigation, and Association of American Physicians. Elected to Honorary Fellowship of the Royal College of Physicians of Ireland, Frederick House, Dublin, Ireland, 2018. Federal Government Advisory Committees
Member of Virology Study Section (1985-1989); |OM Committees on: Smallpox, Polio, Emerging Infections (2003-2009): Chair, BSC, CCID, CDC (2005-2012); Chair, NIAID Council (2008-2012); Member, PCAST H1N1 Working Group (2009); Chair, Recombinant DNA Advisory Committee, NIH (2013-); Chair, NIAID DAIDS HIV Vaccine DSMB (2015-): Member, NIAID Chikungunya DSMB (2017-).
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C. Contributions to Science
My scientific career has focused on the development of antiviral drugs to treat unmet medical needs, particularly herpesvirus infections and influenza, and, orthogonally, the use of herpes simplex virus for gene therapy. Much of this work was performed as the PI for the NIAID CASG.
1. My initial work focused on defining natural history and treatment of herpes simplex virus (HSV) encephalitis (HSE). At the time there were NO therapies for either of these two diseases and little was known of the natural history of either disease. Thus, with the availability of vidarabine, | conducted a controlled clinical trial that demonstrated therapy decreased mortality and improved neurologic outcome. For the very first time, a drug administered parenterally had an antiviral effect. With the availability of acyclovir a direct comparison with vidarabine was performed, indicating significant clinical improvement. These data were the basis of FDA licensure of both drugs for the treatment of HSE. In the conduct of these studies, we proved that PCR was the gold standard for diagnosis, thereby averting the need for brain biopsy. More recently, we completed an international study of HSE to determine if long term valacyclovir improved neurologic outcome. While treatment did not improve neurologic outcome, a great deal was learned about prognosis. | was responsible for all studies, which were funded by the NIH.
a. Whitley RJ, Soong SJ, Dolin R, Galasso GJ, Chien LT, Alford CA and the Collaborative Study Group. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis: National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study. N Engl J Med. 297:289-294, 1977.
b. Whitley Ru, Alford CA Jr, Hirsch MS, Schooley RT, Luby JP, Aoki FY, Hanley D, Nahmias AJ and the NIAID Collaborative Antiviral Study Group. Vidarabine versus acyclovir therapy of herpes simplex encephalitis. N Engl J Med. 314:144-149, 1986.
c. Lakeman FD, Whitley RJ, NIAID Collaborative Antiviral Study Group. Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain biopsied patients and correlation with disease. J Infect Dis. 171:857-863, 1995.
d. Gnann JW, Skoldenberg B, Hart J, Aurelius E, Schliamser S, Studahl M, Eriksson B-M, Hanley D, Aoki F, Jackson AC, Griffiths P, Miedzinski L, Hinthorn D, Anim C, Aksamit A, Cruz-Flores S, Dale I, Cloud G, Jester P, Whitley RJ and the NIAID Collaborative Antiviral Study Group. Herpes simplex encephalitis: Lack of clinical benefit of long-term valacyclovir therapy. CID, Sep 2015; 61(5): 683-91. PMID25956891, PMC4542890.
2. From our studies of HSE, we had a repository of brain and peripheral isolates that could be tested for neurovirulence genes. In a classic bench-to-bedside approach, we engineered HSV to express foreign genes that had not previously been done in a background that indicated replication in tumor models and not in normal brain tissue. Through my own PPG, we performed a series of evaluations leading to an HSV deleted in y:34.5 and expressing human IL-12. We have now initiated our fourth Phase IB clinical trial to determine potential efficacy and safety. These studies were among the first in the world to use an engineered HSV for gene therapy. All studies were funded by the NIH and I was the PI or co-PI.
a. Chou J, Kern ER, Whitley RJ, and Roizman B. Mapping of neurovirulence to protein 34.5 encoded by a diploid herpes simplex virus 1 gene non-essential for growth in cell culture. Science. 250:1262-1266, 1990.
b. Andreansky SS, He B, Gillespie GY, Soroceanu L, Markert J, Roizman B, Whitley RJ. Application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors. Proc Natl Acad Sci USA. 93:11313-11318, 1996. PMID8876132, PMC38054.
c. Parker J, Gillespie GY, Love CE, Randall S, Whitley RJ, Markert JM. Engineered herpes simplex virus expressing interleukin 12 in the treatment of experimental murine tumors. Proc Natl Acad Sci USA. 97:2208-2213, 2000. PMID10681459, PMC 15779.
d. Roth J, Cassady K, Cody J, Parker J, Coleman J, Price K, Peggins J, Grimes S, Powers N, Noker P, Carroll S, Gillespie GY, Whitley RJ, Markert J. Evaluation of the Safety and Biodistribution of M032, an Attenuated HSV-1 Virus Expressing hiL-12, After Intracerebral Administration to Aotus Non-Human Primates. Human Gene Therapy, March 2014. PMID 24649838, PMC4047998.
3. In parallel, | initiated studies of neonatal HSV infections, defining the natural history and value of therapy.
In studies of both vidarabine and acyclovir, funded by the NIH, we demonstrated improved survival and neurologic outcome but only at high dose acyclovir therapy. Again, these data were the basis for FDA licensure and citation for use in the American Academy of Pediatrics (AAP) Red Book. In oral pharmacokinetic
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studies long term suppression with acyclovir was initiated and further clinical improvement was established as assessed by Bailey Developmental Scores. For each of these studies | was either the PI or co-principal investigator.
a. Whitley RJ, Nahmias AJ, Soong SJ, Galasso GG, Fleming CL, Alford CA Jr and the NIAID Collaborative Antiviral Study Group with special assistance from J Connor, Y Bryson and C Linnemann. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics. 66:495-501, 1980.
b. Whitley RJ, Yeager A, Kartus P, Bryson Y, Connor JD, Nahmias AJ, Soong SJ and the NIAID Collaborative Antiviral Study Group: Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy. Pediatrics. 72:778-785, 1983.
c. Kimberlin DW, Lin C-Y, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong S-J, Kiell J, Lakeman FD, Whitley RJ and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 108:230-238, 2001, PMID11483782.
d. Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sanchez PJ, Jacobs RF, Bradley JS, Robinson JL, Shelton M, Dennehy PH, Leach C, Rathore M, Abughali N, Wright P, Frenkel LM, Brady RC, Van Dyke R, Weinier LB, Guzman-Cottrill J, McCarthy CA, Griffin J, Jester P, Parker M, Lakeman FD, Kuo H, Lee C, Cloud GA for the National Institiute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Oral acyclovir suppression and neurodevelopment after neonatal herpes. NEJM 365(14): 1284-1292, October 6, 2011. PMID 21991950, PMC 3250992.
4. Our team next tackled congenital cytomegalovirus (CMV) infection, the most common congenital infection in the developed world. Detailed pharmacokinetic (PK) and pharmacodynamic (PD) studies defined a safe dose that significantly decreased viral load. This dose then became the basis for our controlled clinical trial that proved IV ganciclovir improved hearing, growth, and achieving developmental milestones. Because drug had to be administered IV, we performed PK and PD studies with valganciclovir to establish a dose for long term therapy. With six months of therapy, hearing and Bailey Neurodevelopmental Assessments improved. These are the first data to document efficacy for a chronic viral infection in a newborn child. The data have been amended to the NDA and are the basis for the AAP Red Book recommendation for treatment. All studies were funded by the NIH and | was the PI or Co-PI.
a. Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, Dankner W, Starr S, Pass R, Stagno S, Alford C, Soong SJ, Whitley RJ, Sommadossi JP, and the NIAID Collaborative Antiviral Study Group. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. Clin Pharmacol Ther. 53:15-21, 1993.
b. Kimberlin D, Acosta EP, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang D, Romero JR, Griffin J, Cloud GA, Lakeman FD, Whitley RJ for the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: A pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital CMV disease. J. Infect. Dis., 197:836- 845, 2008. PMID18279073.
c. Acosta EP, Brundage RC, King JR, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang D, Romero JR, Griffin J, Cloud G, Whitley R, Kimberlin DW for the NIAID Collaborative Antiviral Study Group. Ganciclovir Population Pharmacokinetics in Neonates Following Intravenous Administration of Ganciclovir and Oral Administration of a Liquid Valganciclovir Formulation. Clin Pharmacol Ther. 81(6):867-72. June 2007. PMID17392728.
5. With the 2009 H1N1 influenza outbreak, the CASG undertook studies of oseltamavir to define safety through PK and PD studies in infants less than two years of age. These data were the basis for the Emergency Use Authorization issued by the FDA, CDC, EMEA, and WHO for dosing of small babies with oseltamavir. These were the only such studies performed in the world and are the basis for AAP Red Book recommendations. The data have been filed with the FDA as amended to the NDA. These studies were supported by the NIH and | was the PI or Co-PI. More recently, | have developed the RdRp assays with Dr. Prichard for Project 4 of the current application.
a. Acosta EP,Jester P, Gal P, Wimmer J, Wade J, Whitley RJ, Kimberlin DW. Oseltamivir
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dosing for influenza infection in premature neonates. JID, 202(4):563-566, March 2010. PMID20594104, PMC2904429.
b. Kimberlin DW. Acosta EP, Prichard MN, Sanchez PJ, Ampofo K, Lang D, Ashouri N, Vanchiere JA, Abzug MJ, Abughali N, Caserta MT, Englund JA, Sood SK, Spigarelli MG, Bradley JS, Lew J, Michaels MG, Wan W, Cloud G, Jester P, Lakeman F, Whitley RJ. Oseltamivir pharmacokinetics, dosing, and resistance in children from birth to two years of age with influenza. J Infect Dis. 2013 Mar 1;207(5):709- 20. PMID 23230059, PMC23230059.
ce. Kamal MA, Acosta EP, Kimberlin DW, Gibiansky L, Jester P, Niranjan V, Rath B, Clinch B, Sanchez PJ, Ampofo K, Whitley RJ, Rayner CR. The Posology of Oseltamivir in Infants with Influenza Infection Using a Population Pharmacokinetic Approach. Advanced Online Publishing, Clinical Pharmacology and Therapeutics (June 2014), doi: 10.1038/clpt.2014.120. PMID 24865390.
Full list of published work available at: http://www.ncbi.nim.nih.gov/sites/myncbi/tichard.whitley. 1/bibliography/40322964/public/?sort=date&direction= ascending
D. Research Support ACTIVE
HHSN272201100034C (Whitley, Kimberlin Co Pl) 9/28/11-8/15/20
HHS-NIH-NIAID
An adaptive sequential study evaluating prevention of neonatal HSV: Detection of maternal shedding at delivery followed by preemptive antiviral therapy in exposed neonates.
In this project, a multi-institutional team of investigators, known as the Collaborative Antiviral Study Group (CASG), will validate the GenexXpert® HSV polymerase chain reaction (PCR) system by comparing it against standard quantitative PCR and routine viral culture.
HHSN272201100035C (Whitley, Kimberlin Co P!) 9/28/11-8/15/20
HHS-NIH-NIAID
A Phase II 6 Weeks oral Valganciclovir vs Placebo in infants with Congenital CMV infection and hearing loss. In this project, the CASG will identify infants and toddlers with SNHL and then will test these patients’ DBS obtained during the neonatal period for CMV DNA by PCR.
HHSN272201 100036C (Whitley, Gnann Co PI) 9/28/11-8/15/20
HHS-NIH-NIAID
Natural History of Infection Caused by BK Virus (and other Opportunistic Viral Pathogens) in Renal and Renal- Pancreas Transplant Recipients
The primary objective of the study is to determine the safety, tolerability and optimal dose of CMX001 in kidney transplant patients with BKV viremia.
HHSN272201 100037C (Whitley, Kimberlin Co Pl) 9/28/11-8/15/20
HHS-NIH-NIAID
A PK/PD and Resistance Evaluation of Intravenous Ganciclovir in Premature Infants
In this project, a multi-institutional group of investigators, Known as the Collaborative Antiviral Study Group (CASG), will enroll premature subjects who are being treated clinically with intravenous ganciclovir for postnatally or congenitally acquired CMV disease.
HHSN272201100038C (Whitley, Kimberlin Co Pl) 9/28/11-8/15/20
HHS-NIH-NIAID
Adaptive study of CMX-001 in infants with Neonatal Herpes Simplex Virus (HSV)
In this project, a multi-institutional team of investigators, known as the Collaborative Antiviral Study Group (CASG), will define the pharmacokinetics (PK) and concentration response relationship of CMX001 in neonates with HSV CNS disease.
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1U19A1109680-03 (Whitley, P!) 3/1/14-02/28/19 NIH-NIAID
Center for Antiviral Drug Discovery and Development-UAB
Role: Administrative Core: Pl, and Project Director; Project 4.0 — Influenza: Co-PI
UM1 AR065705 (Curtis, Winthrop, MPI) 9/01/14 — 8/31/19
NIH/NIAMS
Safety and Effectiveness of Live Zoster Vaccine in Anti- TNF Users (VERVE)
The Varicella zoster VaccinE (VERVE) trial is a randomized, double-blind, placebo controlled large pragmatic trial to evaluate the immunogenicity, safety and longer-term effectiveness of the live HZ vaccine in arthritis patients receiving anti-TNF therapy
Role: Advisor
NGI 5P30CA013148 (Partridge, Pl) 4/01/16 - 03/31/21 NIH-NCI
Comprehensive Cancer Center Core Support Grant
The major goal of this project is to support cancer research with emphasis on interdisciplinary efforts for the Comprehensive Cancer Center.
Role: Co-Investigator
U54TR001368-01 (Kimberly) 9/01/15 — 8/31/20
NIH/NCATS
UAB Center for Clinical and Translational Science (CCTS)
The UAB CCTS will enhance human health by driving scientific discovery and dialogue across the bench, bedside and community continuum. The CCTS support this overall mission in a highly integrative network of relationships. Success in creating such an environment is dependent upon success in achieving five strategic priorities: 1) enhancing research infrastructure; 2) promoting investigator education, training and development; 3) accelerating discovery across the T1 interface; 4) expanding value-added partnerships; and 5) building sustainability.
Role: Co-Investigator, Project Leader
HHSN272201600017C (Kimberlin, Pl) 7/01/16 — 06/30/21
NIH/NIAID
A Phase II, Single-Stage, Single Arm Investigation of Oral Valganciclovir Therapy in Infants with Asymptomatic Congenital Cytomegalovirus Infection.
Role: Co-Investigator
COMPLETED
N01-Al-30025 (Whitley, Pl) 8/1/03-12/01/13
NIH-NIAID
Clinical Trials for Antiviral Therapies
This contract serves to facilitate the development of promising therapies for treating severe, acute, and chronic human viral diseases that are deemed medically and scientifically important by the NIH-NIAID. This program will facilitate advances in clinical antiviral therapy by rigorously evaluating the efficacy and safety of new therapeutic regimens for serious viral diseases in adult and pediatric patient populations.
5P01-CA 071933-15 (Whitley, Pl) 7/1/09-6/30/15
NIH-NCI
Engineered HSV for the Treatment of Malignant Glioma
The long-term objective of this program project grant, in collaboration with Dr. Bernard Roizman at the University of Chicago, is the design and testing of novel recombinant herpes simplex viruses as vectors of noxious genes for the selective destruction of human glioma cells.
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OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this forma: for each person. DO NOT EXCEED FIVE PAGES.
NAME: OBA.
eRA COMMONS USER NAME (credential, e.g., agency login) (hf
POSITION TITLE ©@)A.®) ©, Drug Discovery
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if Date FIELD OF STUDY
INSTITUTION AND LOCATION applicable) | MMYYYY
OOOO BA. OBAMWG Biology M.S. Organic Chemistry Ph.D. Organic Chemistry
A. Personal Statement Trained as an organic and medicinal chemist, | have almost ®®®®® of drug discovery and management
experience in pharmaceutical industry (8) 3) (A). (&)@ and in an academic and hospital environment ©) @@).©) ©. More recently, in °°"! joined Southern Research, a non-profit research organization, ©G)@.® © in the Drug Discovery Division
where | am responsible for managing the Institute's chemical research initiatives for the identification of new therapies in areas such as oncology, infectious diseases, and neuroscience, involving medicinal chemistry, computational and structural biology efforts. Much of my experience has been dedicated to the discovery of potential agents for the treatment of neurcdegenerative diseases with a concentrated effort in Alzheimer's disease. Some of my significant industrial contributions include acknowledged synthetic efforts of clinical candidates, ©@@.®© and my project leadership in developing early stage hits and rationally designed targets into preclinical candidates and 2 development candidates for the treatment of Alzheimer’s disease and a potential dual agent for the treatment of both anxiety and inflammation. Following industry, | established an academic-based medicinal chemistry and drug discovery laboratory at Oy
preclinical development candidates for the treatment of Alzheimer's disease in which initial hit compounds (ICsc=20 uM) were improved to novel lead and selective compounds (ICso<1nM) with better drug-like profiles than failed clinical candidates. These experiences have allowed me to direct, advise, collaborate and consult for many research or drug discovery programs and bring forward small molecules into preclinical development as potential new therapies. ©) BA). ©) ©
poms,
My scientific record includes more than publications,
presentations and patents.
B. Positions and Honors OEAA.06
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C. Contribution to Science
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D. Research Support Ongoing Research Support
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
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NAME: OO eRA COMMONS USER NAME (credential, e.g., agency iogin): | ee
POSITION TITLE: PROFESSOR
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion
FIELD OF STUDY
INSTITUTION AND LOCATION
A. Personal Statement: | ®@@®@ uses genetic, biochemical, molecular and immunologic apprnachas to (stil the mnolecuan mechanisms pau ay | evolution, virus immunity, viru ‘host interactions
The has longstanding expertise in coronavirus evolution and emergence, replication, virus- rece| , genetics, animal model development and pathogenesis. We have not only made fundamental breakthroughs i in all aspects of coronavirus genetics, biology and immunology, but have designed, developed and tested small molecule inhibitors and vaccines against the emerging CoV.
In this resubmission of Dr. Rich Whitley CETR grant, we continue to develop novel drugs against the emerging coronaviruses, including MERS-CoV, SARS-CoV and pre-epidemic strains.
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B. Positions and Honors.
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OMB No. 0925-0001 and 0925-0002 (Rev. 11/16 Approved Through 10/31/2018)
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NAME: Bostwick, James Robert
eRA COMMONS USER NAME (credential, e.g., agency login):) aa)
POSITION TITLE: Director, HTS Center at Southern Research, Birmingham, AL
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE | Completion (if Date FIELD OF STUDY applicable) | MM/YYYY
INSTITUTION AND LOCATION
Duke University, Durham, NC B.S. 1974 Psychology/Zoology University of Houston, Houston, TX (Dr. Joseph Ph.D. 1980 Biochemistry Eichberg, Advisor)
Baylor College of Medicine, Houston, TX (Dr. Postdoctoral | 1984 Neuroscience Stanley H. Appel, Advisor) Training
A. Personal Statement | have over thirty years of combined experience in academia and the pharmaceutical industry. My breadth of experience includes conducting and managing research, directing scientific operations, and building scientific programs and teams to successfully execute them.
| have routinely managed portfolios of multiple screening projects with combined annual operating budgets of over $4 million and have been involved in over 60 different drug discovery programs. | have primarily engaged in in vitro biochemical and cell-based screening while serving in various roles including group, section, department and project leadership. Moreover, working within global organizations has enabled me to establish the leadership and administrative expertise to manage multi-disciplinary teams across multiple geographic sites and ensure that they retain focus on comprehensive approaches to chemical probe and lead generation.
While al © ©,, | successfully championed, designed and built a US-based HTS group with a capacity to run multiple HTS campaigns per year against a compound collection in excess of a million compounds. This required the establishment of efficient processes throughout the entire value chain of HTS operations including compound management, assay development, screen execution, hit verification and data management to enable high quality output and timely execution of HTS campaigns. With the added ability to utilize diverse technologies and automation, | developed a reputation for producing high quality work in adherence with the scientific rigor demanded for developing and running assays in high throughput mode. In this regard, | seek to implement HTS campaigns utilizing physiologically relevant biological systems and outcome measures in order to optimize translational relevance to secondary and tertiary assays. Subsequently my expertise includes developing biochemical and cell-based assays employing methodologies across multiple technology platforms amenable to HTS. While working at Southern Research | have gained additional experience managing HTS campaigns for anti-infective and anti-cancer targets.
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Current ongoing research projects include drug discovery programs for the invention of antiviral agents for the treatment of emerging and reemerging infections. This work is being conducted as part of aCETR program for which | serve as head of a screening core responsible for conducting high throughput screens and follow up assays to support medicinal chemistry efforts. In the current proposal, | will serve as Core Lead of the Assay Core driving structure activity relationship (SAR) assays to support the Medicinal Chemistry and Lead Development Core and Research Projects. | am also engaged in a drug discovery effort to invent new therapeutic treatments for cystic fibrosis patients with nonsense mutations. |, along with other investigators in the Drug Discovery Division of Southern Research, am currently working in collaboration with Dr. Steven Rowe and Dr. David Bedwell at the University of Alabama at Birmingham to invent a drug that will enhance CFTR expression by targeting suppression of Premature Termination Codons along with inhibition of Nonsense Mediated Decay mechanisms that degrade mRNA containing a PTC.
Example publications:
1. Everts M, Cihlar T, Bostwick JR, Whitley RU. Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model. Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:155-169. doi: 10.1146/annurev-pharmtox-010716-104533. PubMed PMID: 27483339.
2. Mutyam V, Du M, Xue X, Keeling KM, White EL, Bostwick JR, Rasmussen L, Liu B, Mazur M, Hong JS, Falk Libby E, Liang F, Shang H, Mense M, Suto MJ, Bedwell DM, Rowe SM. Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations. American journal of respiratory and critical care medicine. 2016; 194(9):1092-1103. PubMed [journal]PMID: 27104944 PMCID: PMC5114449
3. Rasmussen L, Tigabu B, White EL, Bostwick R, Tower N, Bukreyev A, Rockx B, LeDuc JW, Noah JW. Adapting high-throughput screening methods and assays for biocontainment laboratories, Assay Drug Dev Technol. 13(1):44-54 (2015) PubMed [journal] PMID: 25710545, PMCID: PMC4340648
4. Trivedi S, Liu J, Liu R, Bostwick R. Advances in functional assays for high throughput screening of ion channel targets. Expert opinion on drug discovery. 5(10):995-1006 (2010) PubMed [journal] PMID: 25710545, PMCID: PMC 4340648
B. Positions and Honors Positions and Employment 1985-1992 Assistant Professor, Department of Neurology, Baylor College of Medicine, Houston, TX 1993-1996 Principal Investigator and Group Leader, Fisons Pharmaceuticals, Rochester, NY 1997-1998 Project Leader, Astra Arcus USA, Worcester, MA
1999-2006 Associate Director, High Throughput Screening and Assay Development Section, AstraZeneca Pharmaceuticals, Wilmington, DE 2007-2011 Director, High Throughput Screening and Global Support Department, AstraZeneca
Pharmaceuticals, Wilmington, DE 2011-2012 Executive Director and Site Head, Jubilant Discovery Services, Malvern, PA 2013-present Director, High Throughput Screening Center, Drug Discovery Division, Southern Research Institute, Birmingham, Al.
Other Experience and Professional Memberships
1984-2011 Society for Neuroscience
2004-2011 Society for Biomolecular Sciences (Screening) 2012-date Society for Laboratory Automation and Screening
2004 NIH grant reviewer for the establishment of the Molecular Libraries Screening Center Network (MLSCN; pilot phase) 2007 NIH grant reviewer for the establishment of the Molecular Libraries Probe Production
Network (MLSPN) 2005-2010 NIH grant reviewer of proposals submitted to the MLSCN and MLSPN for execution as HTS assays.
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Having worked most of my career in the pharmaceutical industry, my contributions to science have been in applied rather than basic research. My work has focused on developing and implementing biochemical and cell based assays to enable early phase drug discovery with an emphasis on high throughput screening. As such, | have developed assays in miniaturized formats in conjunction with operational process design and work flow integration to achieve cost effective high throughput screening of large compound libraries. This also involved devising strategies for HTS by combining technological improvements in assay detection and formatting, compound dispensing and bio-reagent production, resulting in reduced cost and time of campaigns. | have had a particular interest in devising HTS assays on targets for which HTS has been problematic. For example, the lack of HTS assays measuring ion channel function has limited drug discovery efforts for these types of targets. My initial interest in calcium channels caused me to be an early adopter of imaging technologies such as the FLIPR (Fluorometric Imaging Plate Reader) in conjunction with calcium sensing dyes. While this approach has proven to be effective for interrogating calcium channels, it was problematic for sodium and potassium channels due to the lack of appropriate dyes. As an alternative approach, | exploited atomic absorption spectroscopy to develop HTS assays for sodium and potassium channels by measuring the flux of surrogate ions lithium and rubidium, respectively. This enabled us to conduct HTS for several such channels, among them NaV1.7. Another example of employing a less conventional approach to HTS was the use of electrochemiluminescence technology (MesoScale) to identify a small-molecule antagonist at the neuromedin U receptor NMUR2. Small molecule antagonist for this peptide receptor had previously not been identified by using more conventional binding assays.
Example publications:
1. Goebel S, Snyder B, Sellati T, Saeed M, Ptak R, Murray M, Bostwick R, Rayner J, Koide F, Kalkeri R. Asensitive virus yield assay for evaluation of Antivirals against Zika Virus. Journal of virological methods. 2016; 238;13-20. PubMed [journal] PMID: 27678028
2. Cochran JN, Diggs PV, Nebane NM, Rasmussen L, White EL, Bostwick R, Maddry JA, Suto MJ, Roberson ED. AlphaScreen HTS and Live-Cell Bioluminescence Resonance Energy Transfer (BRET) Assays for Identification of Tau-Fyn SH3 Interaction Inhibitors for Alzheimer Disease. J Biomol Screen. (2014) 19(10) :1338-1349 PubMed [journal] PMID: 25156556 PMCID: PMC4318572
3. Trivedi S. Dekermendjian K. Julien R. Huang J. Lund PE. Krupp J. Kronqvist R. Larsson O. Bostwick R. Cellular HTS assays for pharmacological characterization of Na(V)1.7 modulators. Assay & Drug Development Technologies. 6(2):167-79 (2008) PubMed [journal] PMID: 18078380
4. Liu JJ. Payza K. Huang J. Liu R. Chen T. Coupal M. Laird JM. Cao CQ. Butterworth J. Lapointe S. Bayrakdarian M. Trivedi S. Bostwick JR. Discovery and pharmacological characterization of a small- molecule antagonist at neuromedin U receptor NMUR2. Journal of Pharmacology & Experimental Therapeutics, 330(1):268-75 (2009) PubMed [journal] PMID: 19369576
URL for full publication list https://www.nebi.nim.nih.gow/sites/mynebi/james.bostwick. 1/bibliography/46458355/public/?sort=date&dire
ction=descending
D. Additional Information: Research Support and/or Scholastic Performance Ongoing Research Support e “Specialized in Vitro Evaluations of Strategies to Combat HIV/AIDS” Principal Investigator: Roger Ptak Agency: NIAID Type: Contract NO1-Al-100010! (SRI14356) Period: 9/17/14 - 9/17/21
The major goal of this project is to evaluate and discover anti-viral compounds. As Director of the HTS Center, Dr. Bostwick's role is to provide oversight of assay development and validation, screening and data analysis.
* 1U19A1109680
Principal Investigator: Dr. Richard Whitley Agency: NIAID Period: 03/01/2014 — 02/28/2019
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Antiviral Drug Discovery and Development Center. The goals of this NIAID program are the development of antiviral drugs for the treatment of emerging and reemerging infections. Specifically, the focus will be on flaviviruses, alphaviruses, corona viruses and influenza. The goal is to identify compounds working through mechanisms that affect viral replication and develop these leads in a translational manner to new human therapeutics. Each of the projects is focused on a viral family deemed critical to NIAID’s focus on Emerging and Re-emerging Infectious Diseases related to biodefense. Unique to this proposal is that in addition to identifying compounds for a particular virus such as West Nile, the strategy will identify 1) mechanisms and targets associated with viral replication and 2) due to the screening strategy outlined (7 assays, same library in 2 years) compounds with activity against multiple viruses will be identified and could be pursued. Dr. Bostwick's role is Leader of the Screening Core.
¢ Identification of New Treatments for Cystic Fibrosis Caused by Premature Termination Codons, Principal Investigator: Mark Suto Agency: O@; Period: 08/31/15 - 8/30/20
6) A)
This is a milestone driven, comprehensive drug discovery effort in collaboration with the University of Alabama at Birmingham to find new therapies for cystic fibrosis patients with a nonsense mutation. As Director of the HTS Center, Dr. Bostwick's role is to provide oversight of assay development, HTS, lead generation screening and associated data analysis.
Completed Research Support
¢ 1RO1A11213664-01A1 sub award 000511529-002 HTS for copper-activated inhibitors against MRSA Principal Investigator: Frank Wolschendorf Agency: NIAID/NIHDHHS Subrecipient Principal Investigator: James R. Bostwick Period: 07/10/16 — 06/30/17
The purpose of this subaward is to develop and validate an assay for use in HTS to screen for copper- activated inhibitors of MRSA.
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OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: 0OW.0O
eRA COMMONS USER NAME (credential, e.g., agency login): OO
POSITION TITLE: Assistant Fellow
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if applicable) Date FIELD OF STUDY INSTITUTION AND LOCATION MMIYYYY OBA.) 6 OBA. 0) © B.Sc. Biochemistry Ph.D. Biological Sciences EMBO Microbiology of Post-Doctoral Bordetella pertusiss Fellowship EMBO Development of a high- Post-Doctoral throughput screening for Fellowship the search of inhibitors of bacterial conjugation
A. Personal Statement
| have extensive experience in the field of infectious diseases, including work on bacteriology, phage biology, virology and molecular biology. My work in this area began ©) GB) A). ©) ©
as head of the Molecular Biology Lab of the same center where | served for three years. During those years as a group leader, | successfully administered several ongoing projects, and established fruitful international collaborations with scientists from the Netherlands, France and Spain, despite the unfavorable research setting imposed by the scarcity of resources for science and the political environment of °®”®®Several projects in which | was involved resulted in successful outcomes (e.g. development of a live attenuated cholera vaccine, the first-time identification of inhibitors of bacterial conjugation, the breakthrough discovery of the role of bacterial oxylipins in pathogenesis), which are supported by resulting peer-reviewed publications and patents. Given the better access to resources to my scientific research, ®)G)).©) © to take advantage of collaborative networks formed through my previous work. Although it required slight disruption of my immediate career (one year’s time), this decision enabled me to advance my scientific work OOA.0O
due to work dedicated to bacteriology and virology, | have recently been promotec to an independent position allowing me to develop my own research program. After only one and a half years in this position | have secured three pilot grants from the ORS
have also published four peer-reviewed
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B. Positions and Honors
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C. Contributions to Science
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: OBA. O
eRA COMMONS USER NAME (credential, e.g., agency login)! ow
POSITION TITLE: Research Associate Professor of Pediatrics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) | MMYYYY OBA.) 6 BS. POAMOG Biology M.S. Biology Ph.D. Microbiology and Immunology M.D. Medicine Residency Clinical Pathology Fellowship Clinical Microbiology
A. Personal Statement
Greater than two decades of engagement with virology in the research and clinical laboratory settings equips me to partner effectively with academic and biopharma colleagues in the advancement of candidate drugs for treatment and prevention of coronavirus (CoV) and other emerging viral diseases. My professional background broadly encompasses interests, research, and clinical activities linked to the pathogenesis, etiology, epidemiology, and prevention of infectious diseases, with primary emphasis on the respiratory and enteric systems. Particular expertise, experience, and skills that prepare me to function as key personnel in the AD°C. program include: (1) PhD in microbiology and immunology (molecular virology emphasis); (2) former PI of an independent research laboratory with blenced foci in basic investigative virology (RNA virus replication mechanisms) and collaborative clinical projects addressing the epidemiology, pathobiology, and vaccine- mediated prevention of acute respiratory illness and gastroenteritis; (3) AD°C investigator and sole focus on CoV biology, including virus-cell interactions and countermeasures, since joining the HAA.0OO
(5) previous service on the VU Institutional Biosafety Committee and Biological Agents in Human Subjects Subcommittee; and (6) history of participation in several multi-site, multi-investigator studies as co- investigator and laboratory lead, including primary scientific responsibility for an active collaboration with the NIH Vaccine Research Center around the design and development of Middle East respiratory system (MERS) CoV vaccines and immunotherapeutics. Thus, | will draw upon a broad virology background and specific experience in CoV basic and translational science to advance program goals of the AD°C consortium.
Relevant peer-reviewed literature: 0) G) A). ©) ©
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B. Positions and Honors
C. Contribution to Science
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D. Research Support
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: ®O@.O@ Ph.D.
eRA COMMONS USER NAME (credential, e.g., agency login): we
POSITION TITLE: Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) MM/YYYY ——— VOMOORA ©) A). &) Pooloay M.S. Biology Ph.D. Biology Postdoctoral Virology/Immunology
A. Personal Statement
My research career has involved investigating numerous and diverse phenomena related to innate immunity, molecular biology, and viral disease. This includes exploring the biology of pattern recognition receptor signaling, the type | interferon response, and the mechanistic roles of innately activated transcription factors. Early in my career | focused on these topics largely in the context of virus-mediated activation, direct antiviral responses, and viral immune evasion. Recently my efforts have shifted to investigating the function and importance of innate immune processes for establishment of adaptive immunity and in the context of antiviral strategies. In light of this my work now commonly employs techniques of drug discovery and development to identify and characterize novel compounds that elicit precisely targeted innate immune reactions useful in the contexts of vaccine enhancement, anti-tumor immunity, and broad-spectrum antiviral activity. This has led to the identification and characterization of novel IRF-activating molecules and a multi-investigator effort to understand how these can be employed in the context of immunotherapeutics. Experimentally | have employed and adapted a broad range of model types including in vitro and ex vivo culture of mammalian cells, mice, and nonhuman primates. | have also utilized and mastered a range of investigative and high content exploratory platforms including transcriptomics (RNAseq and hybridization array), proteomics, and high throughput chemical screening. | also routinely employ and customize numerous cutting edge molecular methodologies such as viral vectors, transposon-mediated transgenics, cell reporters, CRISPR/Cas9-driven genome editing, protein techniques, and viral mutagenesis. My work has integrated these approaches with in vivo examination of adaptive immune responses including antibody and T lymphocyte activities. This scientific background has allowed me to accumulate a valuable research infrastructure of reagents, equipment, and intellectual resources. As such, | am well positioned to lead the studies outlined in this proposal.
B. Positions and Honors
Positions and Employment OAOA.0OO
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. Contributions to Science (*Corresponding Author)
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Ongoing Research Support
None
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Name: Denison, Mark R. eRA COMMONS USER NAME: TOTO)
POSITION TITLE: Professor of Pediatrics, Professor of Pathology, Microbiology & Immunology EDUCATION/TRAINING
INSTITUTION AND LOCATION DEGREE Completion Date | FIELD OF STUDY University of Kansas, Lawrence, KS BA 05/1977 Chemistry / English University of Kansas, Kansas City, KS MD 06/1980 Medicine University of lowa Hospitals, lowa City, IA Residency | 06/1983 Pediatrics
as a ; Postdoctoral Infectious Diseases, University of lowa, lowa City, IA Fellowship 06/1986 Virology
A. Personal Statement
My laboratory studies the replication and pathogenesis of the coronaviruses (CoVs), a family of positive-strand RNA viruses including SARS-CoV and MERS-CoV. MERS-CoV is a zoonotic pathogen currently active in the Middle East and Asia, and is recognized as a potentially pandemic pathogen. Research and training in my laboratory uses the model coronavirus murine hepatitis virus (MHV) as well as SARS-CoV and MERS-CoV, to understand the viral and host determinants of replication and pathogenesis. My research program has defined mechanisms of replicase protein expression and processing, determinants of viral protease functions in replication, virus-induced membrane modifications required for infection, reverse genetics and synthetic genomics of zoonotic coronaviruses, a novel RNA proofreading mechanism during CoV replication, and new vaccine approaches and inhibitors of coronavirus replication. My research has been continually NIH funded since 1987. Particularly relevant to this proposal is our longstanding and highly productive collaboration with the Baric Lab (since 2000) which has resulted in over multiple collaborative and Co-PI R01, U54, P01, U19 and other grants, resulting in over 20 collaborative high impact publications.
Expertise in Antiviral Drug Development. My expertise for directing this project is based on our development of systems to study the determinants of Coronavirus replication, proofreading, fidelity, and evolution, as well as approaches to countermeasures. Our lab was the first to discover that CoVs encode an unprecedented RNA dependent ‘RNA proofreading exonuclease (ExoN) involved in CoV high fidelity replication. We have shown that WT CoVs (SARS-CoV, MHV) are resistant to mutagens and many antiviral nucleosides, while mutant viruses lacking EXON are profoundly sensitive to these agents. Most critically, we demonstrated that WT CoVs (MHV, SARS-CoV) are sensitive to the nucleoside prodrug GS-5734 (remdesivir), suggesting a unique activity against the viral polymerase resistant to ExoN proofreading. That discovery is the basis for the ongoing collaboration with Gilead and UNC, which now has extended to Emory Institute for Drug Development, with the identification of the nucleoside analog EIDD-1931/2802 with preliminary high activity against WT CoVs. Our published studies below demonstrate our team capacity for academic / industry partnerships to move lead compounds forward in all areas of pharmacokinetic, virologic, mechanistic, and in vivo studies toward IND and acquisition of additional funding for preclinical development.
1. Sheahan TP, Sims AS, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva |, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS. Cihlar T, Jordan R, Denison MR, Baric RS. 2017. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Trans Medicine. 9(396): doi:10.1126/scitransimed.aal3653
2. Agostini ML, *Andres EL, Sims AC, Graham RL, Sheahan TP, Lu XT, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, “Baric RS, ‘Denison MR. 2018. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease MBio. 9(2): PMID:29511076
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B. Positions and Honors Positions and Employment
1987-1991 Assistant Professor of Pediatrics, Thomas Jefferson University, Philadelphia, PA
1991-1998 Assistant Professor of Pediatrics, Assistant Professor of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN
1998 - 2005 Associate Professor of Pediatrics, Associate Professor of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN
2005-2011 Professor of Pediatrics, Associate Professor of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN
2011-Present Craig-Weaver Professor of Pediatrics.
Professor of Pathology, Microbiology & Immunology, Election to Professional Societies (Elected Fellow)
1992 Society for Pediatric Research
2011 American Association for the Advancement of Science 2012 American Academy of Microbiology
2012 American Pediatric Society
2016 Association of American Physicians
Public Advisory Committees and Editorial Boards 1994-Present Ad Hoc Reviewer, Experimental Virology, Virology, Virology A, Virology B
2011-2017 Appointed member (2011-2014) and Chair 2014-2017), Microbiology and Infectious Diseases — B Study Section, National Institutes of Health, NIAID
2014-2017 Associate Editor, mBio
2011-2017 Editorial Board, Journal of Virology
2017-Present Member, National Science Advisory Board for Biosecurity (NSABB)
2016-2018 Councilor for Medical Virology, American Society for Virology
Honors and Awards
2001 Vanderbilt University School of Medicine Award for Teaching
201 1-present Craig Weaver Chair in Pediatrics, Vanderbilt University
2012 American Society for Virology, State of Art Symposium
2012 Wedum Memorial Keynote Lecture — American Biosafety Association
2016 American Society for Virology Plenary Symposium — Holland Lecture in Virus Evolution
C. Other Contributions to Science
1. Coronavirus RNA proofreading and replication fidelity in fitness and virulence. RNA viruses have been long considered to be incapable of the type of error-recognition (proofreading) that is critical to DNA- based organisms. We have demonstrated, in contrast to that paradigm, that CoVs encode the first known RNA proofreading 3'-to-5' exoribonuclease in nsp14 (nsp14-ExoN). Genetic inactivation of ExoN (ExoN-) in MHV and SARS-CoV results in replication competent viruses with a 20-fold mutator phenotype. Further, we have collaborated to show that the ExoN(-) mutator phenotype is attenuating in immune competent and compromised mouse models of lethal SARS-CoV maintains ExoN(-) genotype during persistent infection. ExoN proofreading is responsible for CoV resistance to mutagens and nucleoside analogs and that ExoN- viruses are profoundly sensitive to such compounds. Long-term passage of ExoN(-) virus identifies adaptive fidelity mutations in the viral polymerase. Together the studies overturn a long-held dogma that RNA viruses are not capable of proofreading, suggesting a profound new model for fidelity regulation in coronaviruses, and identify a new vulnerability in CoV replication, virulence and pathogenesis that can be exploited in antivirals and vaccines. In support of this we have demonstrated a nucleoside analogue antiviral that is able to overcome ExoN mediated proofreading.
a. Eckerle, L. D., X. Lu, S. M. Sperry, L. Choi, and M. R. Denison. 2007. High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J Virol 81:12135-44. (PMC2169014)
b. Eckerle, L. D., M. M. Becker, R. A. Halpin, K. Li, E. Venter, X. T. Lu, S. Scherbakova, R. L. Graham, R. S. Baric, T. B. Stockwell, D. J. Spiro, and M. R. Denison. 2010. Infidelity of SARS-CoV nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog 6(5): e1000896. doi:10.1371/journal.ppat.1000896. (PMC2865531)
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c. Graham, R. L., M. M. Becker, L.D. Eckerle, M. Bolles, M. R. Denison, and R. S. Baric. 2012. A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model. Nature Med 18:1820-1826. (PMC3518599)
d. Smith, E. C., H. Blanc,, M. Vignuzzi, and M. R. Denison. 2013. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog 9(8): e1003565. (PMC3744431). Faculty of 1000, Spotlight in Nature Reviews Microbiology
2. Coronavirus reverse genetics and synthetic biology. We have maintained a long-term, highly productive collaboration with the laboratory of Ralph Baric at UNC-Chapel Hill. This has resulted in the development and use of reverse genetic systems for MHV and SARS-CoV. We have used synthetic genomics and chimeric spike proteins to assemble and recover a non-cultivatable SARS-like bat coronavirus from only available online sequences, in absence of genetic material. This work involved critical interactions among institutions, investigators and others interested in questions of emerging pathogens and dual-use research, to define pathways for design and testing of novel potential pathogens.
a. Yount, B., M. R. Denison, S. R. Weiss, and R. S. Baric. 2002. Systematic assembly of a full-length infectious CDNA of mouse hepatitis virus strain A59. Journal of Virology 76:11065-78.
b. Yount, B., K. M. Curtis, E. A. Fritz, L. E. Hensley, P. B. Jahrling, E. Prentice, M. R. Denison, T. W. Geisbert, and R. S. Baric. 2003. Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci USA 100(22):12995-3000.
c. Sperry, S. M., L. Kazi, R. L. Graham, R. S. Baric, S. R. Weiss, and M. R. Denison. 2005. Single-amino- acid substitutions in open reading frame (ORF) 1b-nsp14 and ORF 2a proteins of the coronavirus mouse hepatitis virus are attenuating in mice. J Virol 79:3391-400.
d. Becker, M. M., R. L. Graham, E. F. Donaldson, B. Rockx, A. C. Sims, T. Sheahan, R. J. Pickles, D. Corti, R. E. Johnston, R. S. Baric, and M. R. Denison. 2008. Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. Proc Natl Acad Sci U S A 105:19944-9. (PMC2588415)
3. Requirements and mechanisms of coronavirus replicase protein expression. CoVs encode the largest known positive-strand (+) non-segmented RNA genomes. Two-thirds of the genome encodes the replicase- transcriptase gene 1, which is translated from the input (+) genome RNA into replicase polyproteins that are subsequently processed into functional nonstructural proteins (nsps). Studies in my research program use the model CoV, murine hepatitis virus (MHV), and more recently SARS-CoV, to determine the patterns and requirements of expression and processing of the CoV replicase polyprotein into functional proteins. My lab was the first to identify protein processing, as well as the patterns of expression of multiple replicase proteins (nsp1-5, 7-10, 12-16), as well as the activity of CoV proteases (PLP1, nsp5-3CLpro). We also defined the genetics of cleavage site requirements for processing and showed that protein processing or even complete replicase proteins were dispensable for virus replication. Our studies over the past 25 years have demonstrated the profound flexibility of coronavirus protein expression, and identified novel attenuating mutations and deletions in the replicase
a. Denison, M. R. and S. Perlman. 1987. Identification of putative polymerase gene product in cells infected with mouse murine coronavirus A59. Virology 157:565-8.
b. Prentice E., J. McAuliffe, X. T. Lu, K. Subbarao, and M. R. Denison. 2004. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins. J Virol 78:9977-86. (PMC514967)
c. Graham, R. L., A. C. Sims, S. M. Brockway, R. S. Baric, and M. R. Denison. 2005. The nsp2 replicase proteins of murine hepatitis virus and severe acute respiratory syndrome coronavirus are dispensable for viral replication. J Virol 79(21):13399-41 1. (PMC 1262610)
d. Gadlage, M. J., and M. R. Denison. 2010. Exchange of the coronavirus replicase polyprotein cleavage sites alters protease specificity and processing. J Virol. 84(13):6894-8. (PMC2903247)
4. Coronavirus protease functions. All (+) RNA viruses require the activity of virus-encoded proteases to process their replicase proteins into functional intermediate and mature proteins. Coronaviruses encode 2 or 3 proteases, including 1 or 2 papain-like proteases (PLP1, PLP2) in nsp3 and a “3C-like” protease in nsp5. Since MHV encodes 2 PLPs in contrast to 1 PLP in SARS and MERS, we determined if both PLPs were required. Nsp5 is required for 11 cleavage processing events in the polyprotein and has thus been called the “main” protease. We were the first to identify the activity and cleavage sites of nsp5. We have shown that nsp5
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encodes a network of non-conserved residues that regulate the activity of nsp5 in different CoVs. Overall, our studies have identified requirements for CoV proteases and defined new targets for inhibition and attenuation within the proteases.
a. Graham, R. L., and M. R. Denison. 2006. Replication of murine hepatitis virus is regulated by papain-like proteinase 1 processing of nonstructural Proteins 1, 2, and 3. J. Virol. 80: 11610-11620. (PMC1642617)
b. Stobart, C. C., A. S. Lee, X. T. Lu, and M. R. Denison. 2012. Temperature-sensitive mutants and revertants in the coronavirus nonstructural protein 5 protease (3CLpro) define residues involved in long- distance communication and regulation of protease activity. J Virol 86 (9):4801-4810. (PMC3347385)
c. Stobart, C.C., N. R. Sexton, H. Munjal, X. T. Lu, K. L. Molland, S. Tomar, A. D. Mesecar, and M. R. Denison. 2013. Chimeric exchange of coronavirus nsp5 proteases (3CLpro) identifies common and divergent regulatory determinants of protease activity. Journal of virology 87:12611-18. (PMC 3838113).
5. Cell biology of coronavirus infection. Positive-sense RNA viruses replicate in the cytoplasm of infected cells in replication complexes assembled on modified cytoplasmic membranes. We have used genetics and microscopy to show the determinants and interactions of MHV, and SARS-CoV replicase proteins for interactions in replication complexes. Our work defines viral protein and cellular pathway determinants that may be novel targets for interference with virus replication. We have shown that CoV nonstructural proteins co-localize to cytoplasmic complexes associated with ER and viral RNA synthesis, and that CoVs use the autophagy pathway to generate double membrane vesicles as sites of replication. Finally, we have shown that MHV is the first known virus to induced constitutive macropinocytosis via interactions with EGFR, likely required for virus cell-cell movement.
a. Denison, M. R., W. J. M. Spaan, Y. van der Meer, C. A. Gibson, A. C. Sims, E. Prentice, and X. T. Lu. 1999. The putative helicase of the coronavirus mouse hepatitis virus is processed from the replicase gene polyprotein and localizes in complexes that are active in viral RNA synthesis. J Virol 73(8):6862-6871.
b. Brockway, S. M., C. T. Clay, X. T. Lu, and M. R. Denison. 2003. Characterization of the expression, intracellular localization, and replication complex association of the putative mouse hepatitis virus RNA — dependent RNA polymerase. J Virol. 77(19): 10515-10527.
c. Prentice, E., W. G. Jerome, T. Yoshimori, N. Mizushima, and M. R. Denison. 2004. Coronavirus replication complex formation utilizes components of cellular autophagy. J Biol Chem 279:10136-41. PMID: 14699140
d. Freeman, M. C. C. T. Peek, M. M. Becker, E. C. Smith, and M. R. Denison. 2014. Coronaviruses induce entry-independent, continuous macropinocytosis. MBio. 5;5(4):e01340-14. (PMC4128357)
Complete List of Published Work in PubMed (copy and paste into browser for best results) http://www.ncbi.nim.nih.gov/sites/myncbi/mark.denison. 1/bibliography/40445236/public/?sort=date &direction=descending
D. Research Support
Ongoing
NIH-NIAID RO1AI108197-06 Denison, Baric (Co-Pls) 03/01/18-02/28/23 Determinants of Fidelity in Coronavirus Replication and Pathogenesis The goal of this project is to identify the intra and intermolecular determinants of nsp14 mediated fidelity in SARS-CoV and emerging MERS-CoV. This is the continuation of the program to look at the in vitro and in vivo determinants of fidelity and impact on replication, immune evasion, fitness and virulence.
Role: Pl
NIH-NIAID RO1A1132178-01 Sheahan /Baric (Pl) 08/09/17-07/31/22 Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV. The goal of the project is to accelerate the preclinical development of GS-5734 and promote IND licensure as and antiviral against MERS-CoV and related emerging CoVs.
Role: Co-Investigator
U19-Al109680-05 Whitley (Pl) 03/01/14-02/28/19 Antiviral Drug Discovery and Development Center The goal of the program (Center of Excellence) is to establish and test lead candidate inhibitors for coronaviruses, flaviviruses, and influenza viruses. Project 2: Inhibitors of Coronavirus Fidelity and Cap Methylation as Broadly Applicable Therapeutics.
Role: PI Project 2
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Defense Advanced Research and Procurement
Agency DARPA-16-35-INTERCEPT-FP-0068. Vignuzzi (Pl) 03/08/17-03/07/21 Defective Interference of Viral Infectious Diseases using Computational Rationale (DIVIDE & ConqueR) Project: Interference of Coronavirus Replication. The goal of the project is to test novel mechanisms for interference with coronavirus replication using defective viral genomes.
Role: P|
Completed in past 3 years: (Demonstrating past productivity and collaborations)
NIH-NIAID RO1A126603-26 Denison (PI) 09/30/91-04/30/17 Polymerase Proteins in Coronavirus Replication. The goals of this proposal were to elucidate the mechanism of the coronavirus replicase proteins in regulating virus replication. Resulted in publications on replicase polyprotein processing, identification of viral proteases and determinants, identification of polymerase and proofreading exonuclease activities, and initiate studies on cell biology and countermeasures against SARS-CoV
Role: P|
U54 Al057157-6-10 NIH-NIAID Sparling (Pl) 03/01/09-02/28/14 Southeast Regional Center for Emerging Infections and Biodefense.
Countermeasures for Coronavirus Infection. Collaboration that developed ExoN-minus viruses for further testing and demonstrated sensitivity of mutator viruses to mutagens, as well as attenuation of mutator genotype.
Role: P! (Baric Co-I)
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NAME: (LLOO@OG POSITION TITLE: Professor
eRA COMMONS USER tid
EDUCATION/TRAINING
DEGREE
INSTITUTION AND LOCATION FIELD OF'STUBY’
Political Science Anatomy Medicine
Cell & Developmental Biology
Medicine & Infectious Diseases
School of Public Health
A. Personal Statement My laboratory has extensive experience in dissecting mechanisms of viral pathogenesis and the host immune response for a number of pathogens of medical relevance. In particular, we have significant expertise in studying the pathogenesis of flaviviruses, and have established many of the key mouse models of disease. | have been working in the Flavivirus field for more than , which includes the study of Dengue, West Nile virus, and Japanese encephalitis viruses, and more recently on Zika virus. We have significant experience in dissecting mechanisms of innate and adaptive immunity in protection and pathogenesis. Relevant to this application is the following: (a) We established and recently published the first mouse model of in utero transmission of Zika virus as well as a separate pathogenesis model in adult mice; (b) We have a large collection of African, Asian, and contemporary Latin American Zika virus strains for use in these studies; (c) We have vast expertise in Zika virus biology and pathogenesis. We have recently generated an immunocompetent mouse model of Zika virus infection and vertical
B. Positions and Honors
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Full publication li . itch Support
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DEGREE END DATE (if applicable) |_ MM/IYYYY
INSTITUTION AND LOCATION
FIELD OF STUDY
Pharmaceutical Sciences Pharmacokinetics &
Drug Delivery Adenoviral Gene Therap
A. Personal Statement
{© O@2HG, | will bring my organizational and content-related expertise to bear on AD3C's Administrative Core. | have served in this role in our current CETR and helped facilitate multiple high throughput screens and medicinal chemistry efforts for antiviral drug discovery, resulting in several Sa
applications, lead molecules and an IND application. This role has built on my capacity as LAER. in which | interface with a wide range of scientists involved in the
drug discovery and development process, with a main focus on projects in oncology and a few other projects focusing on infectious diseases and neurodegenerative disorders. (CRT a TNE . |am trained in the pharmaceutical sciences and have a broad range of publications in drug delivery, adenovirus-based gene therapy as well as nanotechnology in cancer, highlighting my experience in interdisciplinary research teams. | have been involved as the liaison for UAB's Center for Clinical and Translational Science (CCTS)’s drug discovery component, organizing pilot grant programs and educational opportunities in drug discovery and development. | am also
serving as the co-director for the IND/IDE consulting service that the CCTS offers to investigators on campus, giving me regulatory expertise for investigator-initiated trials.
B. Positions and Honors
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C. Contributions to Science
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omplete List of Published Work in My Bibliography:
D. Additional Information: Research Support and/or Scholastic Performance
Ongoing Research Support
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NAME: OBA. 0) ©
eRA COMMONS USER NAME (credential, e.g., agency login): o@
POSITION TITLE: Research Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if Date FIELD OF STUDY applicable) | MM/YYYY
INSTITUTION AND LOCATION
HOMO Bs. ®OAO@ Biology Ph.D. Virology Postdoctoral Virology Postdoctoral Virology
A. Personal Statement
Within the| ©) G)@).®)@, my recent studies have focused on the analysis of the in vitro and in vivo effects of short-term and persistent infections involving attenuated coronaviruses. In addition, my work has explored the utility of using attenuated viruses, specifically ExoN-inactivated and transcriptional regulatory sequence-rewired viruses, as platforms for vaccines that protect against lethal infections. My work has utilized a broad range of experimental strategies, including: in vivo pathogenesis and vaccination in young, aged, and immunocompromised models of disease; sequence analysis, including the identification and analysis of mutations in viral genomes, particularly those accumulated in recombinant viruses over passage in vivo; and fitness studies, including viral competition, persistent infection, and serial passage both in vitro and in vivo. Additionally, my work in both my post-doctoral and my graduate positions afforded me substantial experience in utilizing coronavirus infectious cDNA systems to predict, engineer, and analyze changes to coronavirus genomes in both in vitro and in vivo models, including analyzing the accumulation of mutations in viruses that adapt over passage. | also have extensive experience in generating and preparing viral RNA for sequence analysis (Sanger- based, real-time, and next-generation sequencing platforms). | have generated and optimized a series of real- time assays to evaluate different viral RNA species in the context of infection as well as host markers of apoptosis, necrosis, and immune recruitment following viral infection and/or challenge with antiviral candidates. These skills and experiences will aid in the analysis of viral and cellular RNA species to identify differentiating features in infected vs. uninfected cells and animals and treated vs. untreated conditions.
B. Positions and Honors ) G) (A). ©) ©)
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lete List of Publi: Work in NCBI iblios
D. Research Support iIngoin rch
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NAME:| ©G)@.@)@
eRA COMMONS USER NAME (credential, e.g., agency login):| oo POSITION TITLE: Professor of Genetics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion (if Date FIELD OF STUDY applicable) | MM/YYYY
INSTITUTION AND LOCATION
OOMOO FB HOOAMwMe Biology Ph.D. Immunology Postdoc Virology
A. Personal Statement
©)@)@).) © research team uses advanced molecular virology and immunology techniques, as well as animal models of virus-induced disease, to study the pathogenesis of mosquito-borne and respiratory viruses. Dr. p2“9has studied viral pathogenesis and immunology for ®@)@. ©) his research program has been focused on understanding the viral and host factors that contribute to the pathogenesis of mosquito borne arboviruses, such as Venezuelan equine encephalitis virus (VEEV), chikungunya virus (CHIKV), Ross River virus (RRV) and Zika virus (ZIKV). He also studies respiratory viruses, such as influenza A virus (IAV), MERS-CoV, and SARS-CoV. Through these research efforts,© @)@).)@ team has developed new models of virus-induced disease, including models of CHIKV-induced arthritis, as well as SARS-CoV and MERS-CoV induced respiratory disease. © @@.© © laboratory has used these models to make significant contributions to the field's understanding of how these viruses interact with the host innate and adaptive immune system, including factors that contribute to virus-induced arthritis or respiratory immune pathology. These systems have also allowed him to test the efficacy of both antiviral molecules and vaccines against a wide variety of viruses, including CHIKV. Through these efforts, the ab has developed extensive expertise in analyzing alphavirus-induced disease outcomes, as well as assays and expertise for quantifying viral replication and analyzing specific stages in the viral replication cycle. Therefore, MP MOsng his research team provide key expertise that will allow this program to accomplish its goal of developing highly effective antiviral compounds for treating alpbhavirus-induced disease, and developing combination therapies that target both the virus and the host inflammatory response.
B. Positions and Honors
Positions and Employment O@A.0) ©
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C. Contribution to Science
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Complete List of Published Work in MyBibliography:
D. Research Support ACTIVE:
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Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: SONS)
RA COMMONS USER NAME (credential, e.g., agency login): POSITION TITLE: Assistant professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE (if applicable)
Completion
INSTITUTION AND LOCATION FIELD OF STUDY
Molecular Biology
A. Personal Statement
My lab studies multiple facets of the interaction of flaviviruses with the infected host, focusing primarily on the dengue viruses, West Nile virus, and, most recently, Zika virus. My lab has examined ZIKV tropism, persistence, and immune response in infected rhesus macaques, and we have further extended this model to examine ZIKV infection during pregnancy and characterize fetal and placental tropism and pathogenesis. Previously, | have initiated and contributed to multiple collaborative studies identifying important cellular proteins/ pathways involved in flaviviruses infection. This work has been extended to several large programs directed at the discovery af anti-viral molecules, in which | currently serve as a co-investigator. Most recently, | have acted as co-investigator in a project to develop novel vaccine adjuvants targeting specific arms of innate immune signaling pathways. These adjuvants are being evaluated with virus-like particle based vaccines specific for individual flaviviruses (WNV, DENV, WNV, and ZIKV), including in the NHP model of ZIKV infection. Therefore, on going work within my lab is focused on in vivo ZIKV replication and mechanism of pathogenesis, analysis of the immune response, and development of both therapeutic and prophylactic interventions. This expertise, together with that of the other project personnel and the extensive expertise at the Oregon National Primate Research Center, makes me well positioned to contribute to this study.
B. Positions and Honors
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C. Contribution to Science
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POSITION TITLE: POAOO ‘RA COMMONS USER NAME (credential, e.g., agency ‘ocr: ES
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
A. Personal Statement
My research has focused on discovery and development of antiviral compounds. | have experience in all facets of drug development including target discovery and validation through development of cell-based and biochemical assays to measure virus replication or enzymatic activity of key proteins required for replication or pathogenesis. In addition, | have developed animal models of virus infection with quantitative endpoints for measuring antiviral efficacy of lead compounds. | have experience supporting lead optimization of preclinical compounds, and knowledge of scale up manufacturing of drug substance and drug product, safety pharmacology, regulatory requirements for IND and NDA filings and clinical development of antiviral compounds. !am responsible for developing antiviral therapeutics for acute virus infections including respiratory viruses and emerging and neglected viruses. | have a unique opportunity to leverag'
proprietary compounds and expertise to develop compounds for emerging and neglected viruses including coronaviruses such as MERS-CoV.
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C. Contribution to Science
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bi
D. Research Support My work is supported by OOM Bana | have no federal support.
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NAME: EREOO@ we eRA COMMONS USER NAME (credential, e.g., agency login): POSITION TITLE: Associate Professor of Immunology and Microbiology
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE (if applicable)
Completion
INSTITUTION AND LOCATION REID Cee
Molecular Biology
LA. Biology
Ph.D. Microbiology/Immunol.
Postdoctoral Viral immunology/viral pathogenesis
A. Personal Statement
My laboratory investigates mechanisms of infectious disease pathogenesis. We use genetic, molecular, cellular, and immunological approaches to define molecular mechanisms of pathogenesis and to evaluate novel therapeutic interventions. Pertinent to this application, my laboratory has developed mouse models of Ross River virus (RRV) and chikungunya virus (CHIKV)-induced rheumatic disease that recapitulate important aspects of acute and chronic RRV and CHIKV disease in humans. In addition, we also use cell culture studies and mice to investigate mechanisms of neurological disease associated with neurotropic viruses such as Venezuelan equine encephalitis virus (VEEV), West Nile virus, and Zika virus.
The purpose of the Antiviral Drug Discovery and Development Center (AD3C) is to discover potential new drugs which could be used to treat infections such as West Nile virus and influenza that routinely infect US citizens, and for which we have limited or no treatments. We also will strive to develop therapies for emerging infections such as coronaviruses, dengue and chikungunya which pose risks for traveling US citizens or could be imported into the country by others.
B. Positions and Honors
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C. Contribution to Science
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Complete List of Published Work in ibli
D. Research Support
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OMB No. 0$25-0001/0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: OGNAE}}
eRA COMMONS USER NAME (credential, e.g., agency login) HE POSITION TITLE: Professo! ©@)@.@@ OHSU
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE | Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) | MM/YYYY
BS Biological Sciences PhD Microbiology Postdoc
A. Personal Statement
{YY BO@H06 is a senior molecular virologist with ove) diapers and reviews on a variety of topics in virology and immunology. The primary focus of OO Mrese nters on the molecular pathogenesis and
immune response to viruses including herpesviruses, oie and retroviruses. OOW.OO has used
molecular and animal model approaches over the pas ears to characterize cytomegalovirus (CMV) retrovirus and flavivirus immunology and pathogenesis. These studies have been supported over the years b! RO1s, several contracts and program projects at the )
B. Positions & Honors
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C. Contributions to Science
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Complete List of Published Work in My Bibl
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NAME: @O@OO eRA COMMONS USER NAME (credential, e.g., agency login) 2 POSITION TITLE: Professor of Pharmacology, Emory University School of Medicine
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
Completion INSTITUTION AND LOCATION ( FIELD OF STUDY
Chemistry
Physical Organic Chemistry
Organic Chemistry Organic Chemistry Cell Biology
A. Personal Statement | currently hold the 1S Professor of Pharmaco Emory University School of Medicine.
these roles | have directed the establishment of a freestanding drug discovery and development company inside the Universi
| have played a major role in the discovery, development and implementation of modern antiviral therapy. Pri to
In my capacity as | GIANNI will oversse the work done as part of the chemistry and bioanalytical cores. | will also provide insights and guidance for the SARS/MERS project. My
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B. Positions and Honors
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C. Contribution to Science
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eeu of Published Work in wed
D. Research Support
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NAME: Pathak, Ashish Kumar
eRA COMMONS USER NAME (credential, e.g., agency login)? OO
POSITION TITLE: Advanced Scientist
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion 5 7 Date FIELD OF STUDY INSTITUTION AND LOCATION (if applicable) MMIYYYY University of Lucknow, Lucknow, India B.Sc. 06/1985 | Chemistry, Physics, Mathematics University of Lucknow, Lucknow, India M.Sc. 07/1987 | Organic Chemistry University of Lucknow, Lucknow, India Ph.D. 02/1993 | Organic Chemistry Central Institute of Medicinal and Aromatic Plants, Post-doctoral | 01/1995 | Phytochemistry/ Lucknow, India Medicinal Chemistry National Institute of Health Sciences, Division of Post-doctoral 07/1996 | Synthetic Organic Organic Chemistry, Tokyo, Japan Chemistry Southern Research, Drug Discovery Division, Post-doctoral 03/2000 | Carbohydrate/Natural Birmingham, AL, USA product/Medicinal chemistry
A. Personal Statement
| have the expertise, leadership and motivation necessary to successfully carry out chemistry approaches in drug discovery. In various positions at research laboratories in India, Japan and here in the USA for last two decades, | have carried out research in various aspects of organic/medicinal chemistry and specifically in synthetic carbohydrate chemistry and small molecule drug discovery. As a principal synthetic chemist on several previous university- and NIH- funded grants and as PI for two R21 grants, | laid the groundwork for several research projects. My research team has worked on a) anti-mycobacterial glycosyltransferases competitive inhibitors; b) semi-synthetic development of Q. saponins preparation GPI-0100 for Galenica Pharmaceuticals and for development of saponin-based adjuvants for Marburg virus vaccine preparation; and c) saponin-based vaccine adjuvants for cancer and bacterial vaccines. Currently, my research group executes internally and externally funded projects in the area of small molecule drug discovery, saponins as immune stimulants and carbohydrate synthesis. | am also the scientist responsible for Southern Research's parallel synthesis laboratory. In my experience as Assistant Professor, | supervised several Graduate students’ thesis projects in Chemistry at Western Illinois University. In addition, | successfully administered research projects (e.g. staffing, research protections, budget), collaborated with other researchers, and produced 60+ peer-reviewed publications and patent applications. | am a project leader for medicinal chemistry programs in several drug discovery programs sponsored by Alabama Drug Discovery Alliance (ADDA), a joint collaboration between Southern Research (SR) and University of Alabama at Birmingham (UAB), which are in early stage to lead development on various targets for diseases such as cancer and anti-infectives. As a result of these previous experiences, | am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. | also have extensive experience in supervising and executing both intramural and extramural research projects. | have a demonstrated record of success and productivity, and my expertise has prepared me to be PI of the Medicinal Chemistry Core of the Antiviral Drug Discovery and Development Center (AD3C), a collaborative effort between SR and the UAB. This program focuses on developing novel small molecule therapeutics for emerging and re-emerging viral infections against Dengue viruses (DENV), West Nile
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virus (WNV), Severe Acute Respiratory Syndrome virus (SARS-CoV), Chikungunya virus (CHIKV), Venezuelan
Equine 300K+
12
Encephalitis virus (VEEV) and Influenza viruses using high-throughput screening (HTS) on library of compounds, and follow-up using medicinal chemistry techniques.
Benzo Annulenes as Antiviral Agents. A.K. Pathak, S.K. Ahmed, C.E. Augelli-Szafran, J.A. Maddry. US Patent Application No. 62/457,653 dated 2017/02/10.
R. Galemmo, A. West, J.A. Maddry, S. Ananthan, A.K. Pathak and J. Valiyaveettil. Triazolopyridazine compounds, use as inhibitors of the kinase LRRK2, and methods for preparation thereof. US Patent 9,187,484 dated 2015/11/17.
A.K. Pathak, J.A. Benitez, A.J. Silva-Benitez. Small molecule inhibitors of bacterial motility and a high throughput screening assay for their identification. US Patent 8,940,740 dated 2015/1/27.
B. Severson, D.H. Chung, C.B. Jonsson, E.L. White, L. Rasmussen, C.B. Maddox, S. Ananthan, A.K. Pathak, J.A. Maddry. Anti-viral treatment and assay to screen for anti-viral agent. International Publication No. WO/2011/097607A1.
B. Positions and Honors Positions and Employment
1992-1
1993-1
1995-1 1996-1
1997-2!
2000-21
2005-21 2009-21
2011-
2013-
993 Senior Research Fellow, Ceniral Institute of Medicinal and Aromatic Plants, Council of Scientific and Industrial Research (CSIR), India.
995 Research Associate Fellow, Central Institute of Medicinal and Aromatic Plants, Council of Scientific and Industrial Research (CSIR), India.
996 Science and Technology Agency Fellow (STA), National Institute of Health Sciences, Tokyo.
997 Senior Research Associate, Central Institute of Medicinal and Aromatic Plants, Council of Scientific and Industrial Research (CSIR), India.
000 Research Associate, Medicinal Chemistry Group, Drug Discovery Division, Southern Research Institute, Birmingham, AL.
005 Research Scientist, Medicinal Chemistry Group, Drug Discovery Division, Southern Research Institute, Birmingham, AL.
008 Assistant Professor, Department of Chemistry, Western Illinois University, Macomb, IL.
013 Research Scientist, Chemistry Department, Drug Discovery Division, Southern Research Institute, Birmingham, AL. Adjunct Professor, Department of Chemistry, University of Alabama at Birmingham (UAB), Birmingham, AL. Advanced Scientist, Chemistry Department, Drug Discovery Division, Southern Research, Birmingham, AL.
Other Experiences and Professional Memberships
2002 — Member, American Chemical Society (ACS)
2005 - 2008 Member, Arts & Science College Faculty Council Committee, Western Illinois University, Macomb, IL
2007 - 2008 Senator, WIU Faculty Senate, Western Illinois University, Macomb, IL
2013 Mail Reviewer, multi-project grant applications RFA-AI-12-048, “Immune Mechanisms of Virus Control (U19)”. NIAID Immune Mechanisms of Virus Control Program (IMVC), NIH
2014 Reviewer, Contract BAA-NIHAI2013168: Adjuvant Discovery Program (2014), NIAID - ZAI1 QV-| (C1), NIH
2016 — Member, International Society of Antiviral Research (ICAR)
Honors
1991 Senior Research Fellow, Council of Scientific and Industrial Research (CSIR), New Delhi, India
1993 Research Associate, Council of Scientific and Industrial Research (CSIR), New Delhi, India
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1995 Science and Technology Agency Fellowship (STA Fellowship), Research and Development
Corporation of Japan (JRDC), Japan through Japan International Science and Technology Exchange Center
1996 Pool Officer, Council of Scientific and Industrial Research (CSIR), New Delhi, India 2010 Innovation Excellence Award, Drug Discovery Division, Southern Research, Birmingham, AL
C. Contribution to Science
1.
During my Postdoctoral experience, | was trained as an organic/medicinal chemistry, firstly as a natural product chemist in artemisinin project that resulted in antimalarial drug Emal (Arteether), and then in asymmetric synthesis using chiral auxiliaries. During my first independent position as Research Scientist at Southern Research, | was involved in developing disaccharide probes/inhibitors to study glycosyltransferases in cell wall of Mycobacterium tuberculosis. These works have produced several publications and presentations.
1. A.K. Pathak, V. Pathak and R.C. Reynolds. Solution Phase Parallel Synthesis of Acyclic Nucleoside Libraries of Purine, Pyrimidine and Triazole Acetamides. ACS Comb. Sci. 16, 485-493 (2014). PMID: 24933643
2. A.K. Pathak, V. Pathak, L.E. Seitz, W.J. Suling and R.C. Reynolds. 6-Oxo and 6-thio purine analogs as antimycobacterial agents. Bioorg. Med. Chem. 21, 1685-1695 (2013). PMID: 23434367
3. K.C. Reddy, N. Padmaja, V. Pathak and A.K. Pathak. Concise synthesis of an arabinofuranose hexasaccharide present in the cell wall of Mycobacterium tuberculosis. Tetrahedron Lett. 53, 2461-— 2464 (2012).
4. A.K. Pathak, V. Pathak, W. J. Suling, J. R. Riordan, S. S. Gurcha, G. S. Besra and R. C. Reynolds. Synthesis of deoxygenated (a 1->5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis. Bioorg. Med. Chem. 17, 872-881 (2009). PMID: 19056279
| led medicinal chemistry efforts ina company contract to design and synthesize Quillaic acid saponin analog GPI-0100 as vaccine adjuvant which is in Phase-IIl clinical trial for several anti-viral, antibacterial and anti- cancer vaccines. Later, | independently developed analogs of Quillaic acid and Gypsogenin as immune agonists to be used in vaccines under two R21 grants funded through NIAID, NIH as Pl. Work is still in progress to develop some hybrid adjuvants based on a hypothesis that synergy of two or more agonist ligands will activate different compartment of immune system with enhanced effects. During the development of this project, a new method to assemble oligosaccharides was also developed which has been used to assemble oligosaccharides of biological interest.
1. A.K. Pathak, V. Pathak and R.D. May. Vaccine compositions for Marburg virus. US Patent Publication No. US20120136142.
2. C.K. Yerneni, V. Pathak and A.K. Pathak. Imidazolium cation supported solution-phase assembly of homo-linear a(1—+6)-linked octamannoside — An efficient alternate approach for oligosaccharide synthesis. J. Org. Chem. 74, 6307-6310 (2009). PMID: 19624152
3. DJ. Marciani, R.C. Reynolds, A.K. Pathak, K. Finley-Woodman and R.D. May. Fractionation, structural studies, and immunological characterization of the semi-synthetic Quillaja saponins derivative GPI-0100. Vaccine 21, 3961-71 (2003). PMID: 12922132
4. D.J. Marciani, J.B. Press, R.C. Reynolds, A.K. Pathak, V. Pathak, L.E. Gundy, J.T. Farmer, M.S. Koratich and R.D. May. Development of semisynthetic triterpenoid saponin derivatives with immune stimulating activily. Vaccine, 18, 3141 (2000). PMID: 10856794
| lead medicinal chemistry efforts in several projects in anti-infective drug discovery area funded in-house or through NIH. Inhibition of bacterial biofilm is an important target and my lab has developed some quinazoline- based molecules which are being further developed as leads. My group is also involved in projects related to anti-viral drug discovery and currently | lead the Medicinal Chemistry Core for the Antiviral Drug Discovery and Development Center funded through NIAID, NIH. We are developing hits from high-throughput screens
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against flavi, corona, alpha and influenza viruses. These hit molecules can be used as probes to study viral
targets and will be further developed as lead molecules to treat these infections.
1. Benzo Annulenes as Antiviral Agents. A.K. Pathak, S.K. Ahmed, C.E. Augelli-Szafran, J.A. Maddry. US Patent Application No. 62/457,653 dated 2017/02/10.
2. C.W. Evans, C. Atkins. A.K. Pathak, B.E. Gilbert, JW. Noah. Benzimidazole analogs inhibit respiratory syncytial virus G protein function. Antiviral Res. 121, 31-38 (2015). PMID: 26116756
3. L. Rasmussen, E. L. White, A. Pathak, J. C. Ayala, H. Wang, J.-H. Wu, J. A. Benitez and A. J. Silva. A High Throughput Screening Assay for Inhibitors of Bacterial Motility Identifies a Novel inhibitor of the Na+- driven Flagellar Motor and Virulence Gene Expression in Vibrio cholera. Antimicrob, Agents Chemother. 55, 4134-4143 (2011). PMID: 21709090
4. L. Wen, J. N Chmielowski, K. C. Bohn, J.-K. Huang, Y. N. Timsina, P. C. Chand and A. K. Pathak.
Functional expression of Francisella tularensis FabH and Fabl, potential antibacterial targets. Protein Expr. Purif, 65, 83-91 (2009). PMID: 19095065
Complete List of Published Work in My Bibliography: http://www. ncbi.nim.nih.gov/myncbi/browse/collection/44204623/?sort=date&direction=descending
D. Research Support
Ongoing Research Support Southern Research-Sponsored Internal Research Projects
1U19A1109680-01 Prof. R.J. Whitely (Pl) 03/01/2014 — 02/28/2019
NIH/NIAID
Antiviral Drug Discovery and Development Center
The herein proposed Center of Excellence for Translational Research (CETR), which will be named the Antiviral Drug Discovery and Development Center (AD3C) has, at its center, the theme to develop new small molecule therapeutics for emerging and re-emerging viral infections. Translational research will focus on the inhibition of viral replication, especially viral polymerase.
Role: Medicinal Chemistry Core Pl/Senior Medicinal Chemist
ADDA program SR-UAB collaboration 01/01/2015 — Ongoing TB Siderophore as a new target for antimycobacterial drug discovery. Role: Project Leader (Medicinal Chemistry)
ADDA program SR-UAB collaboration 01/01/2016 — Ongoing Development of a high throughput screen for inhibitors of EMT, lead generation and optimization. Role: Project Leader (Medicinal Chemistry)
ADDA program SR-UAB collaboration 01/01/2017 — Ongoing Novel antivirals targeting the non-structural protein 1 of influenza. Role; Project Leader (Medicinal Chemistry)
Completed Research Supports
1R21A1101924-01 Ashish K. Pathak (MPI, Contact Pl) 08/06/2012— 07/31/2015
NIH/NIAID
Synthetic Gypsogenin Saponins as Synergistic Vaccine Adjuvants
The major goal of this project was to develop semi-synthetic Gypsogenin saponins as synergistic immune agonists and vaccine adjuvants.
Role: Principal Investigator in a Multi-P! grant (Other Pl: Dr. Michael J. Fuller)
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH
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NAME:Prichard, Mark Neal eRA COMMONS USER NAME (credential, e.g., agency login)! OO
|
POSITION TITLE:Professor of Pediatrics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
Completion DEGREE i ; Date FIELD OF STUDY INSTITUTION AND LOCATION (if applicable) MM/YYYY University of Minnesota, Minneapolis, MN B.S. 06/1987 Microbiology University of Michigan, Ann Arbor, MI M.S. 05/1989 Microbiology University of Michigan, Ann Arbor, MI Ph.D. 08/1992 Microbiology/Immunology Stanford University, Stanford, CA Postdoctoral 09/1996 Molecular Virology
A. Personal Statement
The goal of the application is to further develop a novel inhibitors of the influenza virus RNA dependent RNA polymerase. | am the Principal Investigator of a long standing contract from the NIAID and am responsible for evaluating antiviral compounds against the DNA viruses, including the herpesviruses, poxviruses, polyomaviruses, and papillomaviruses. My laboratory also works with adenovirus and influenza virus on a regular basis. | currently serve as the Director of the Molecular Diagnostic Laboratory where | oversee the diagnosis of viral infections for Children’s Hospital of Alabama. Most importantly, my 25 years of experience in the development of new antiviral drugs has helped me to understand the potential of interdisciplinary research and manage successful collaborations. This experience helps me to construct realistic research plans, timelines, and budgets. My laboratory possesses all the virus isolates and clinical isolates required for the evaluation of influenza virus compounds. This work will build on our previously published work with combination therapy for influenza virus infections.
1. Basu, A, Antanasijevic, A, Wang, M, Li, B, Mills, D M, Ames, J A, Nash, P J, Williams, J D, Peet, N P, Moir, D T, Prichard, MN, Keith, K A, Barnard, DL, Caffrey, M, Rong, L, and Bowlin, TL. New small molecule entry inhibitors targeting hemagglutinin-mediated influenza a virus fusion. J. Virol. 2014;88(3):1447-60. PubMed PMID: 24198411; PubMed Central PMCID: PMC391 1584.
2. Kimberlin DW, Acosta EP, Prichard MN, Sanchez PJ, Ampofo K, Lang D, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013;207(5):709-20. PubMed PMID: 23230059; PubMed Central PMCID: PMC3563309.
3. Nguyen JT, Hoopes JD, Le MH, Smee DF, Patick AK, Faix DJ, Blair PJ, de Jong MD, Prichard MN and Went GT. Triple combination of amantadine, ribavirin, and oseltamivir is highly active and synergistic against drug resistant influenza virus strains in vitro. PLoS One. 2010;5(2):e9332. PubMed Central PMCID: PMC2825274.
4. Nguyen JT, Hoopes JD, Smee DF, Prichard MN, Driebe EM, Engelthaler DM, et al. Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza virus strains in vitro. Antimicrob Agents Chemother. 2009;53(10):4115-26. PubMed Central PMCID: 2764153.
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B. Positions and Honors Positions and Employment
2017 Tenure, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
2012- Director, University of Alabama Health Services Foundation Molecular Diagnostic Laboratory 2008- Professor, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 2007- Assoc. Professor, Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, AL 2006- Scientist, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 2006- Graduate Faculty Member, University of Alabama at Birmingham, Birmingham, AL
2006- Assoc. Professor, Dept. of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 2003-08 Assoc. Professor, Dept. of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 1999-2002 Senior Scientist, Medilmmune Vaccines, Inc., Mountain View, CA
1997-99 Senior Research Scientist, Iconix Pharmaceuticals, Mountain View, CA
1996-97 Research Scientist, Hybridon, Cambridge, MA
Other Experience and Professional Memberships University of Alabama at Birmingham Healthcare Leadership Academy 2013-2014
Appointed as an Editor of Antiviral Research 2012- Program Chair, International Conference for Antiviral Research 2012- Appointed to Editorial Board, Journal of Infectious Diseases 2012- Pan American Society for Clinical Virology 2012- American Society for Microbiology 1987- International Society for Antiviral Research 1987- American Society for Virology 2006- American Association for the Advancement of Science 1999-
Honors William Prusoff Young Investigator Award; International Society for Antiviral Research 2009 Program Chair for the International Conference on Antiviral Research 2012-2017 Elected to Board of Directors, International Society for Antiviral Research 2009-2012 Editorial Board Antiviral Research 2009-present Editor, Antiviral Research 2012-present Editorial Advisory Board, Journal of Infectious Diseases 2010-present
C. Contributions to Science
Work in my laboratory has focused on three major themes related to the development of new therapies for the treatment of viral infections.
1. The first major theme is to collaborate with interdisciplinary teams of investigators to help select molecules with optimal antiviral activity against a broad array of DNA viruses and provide preclinical data to support human trials. Preclinical work performed in my laboratory helped to support the advancement into human clinical trials of maribavir (CMV infections), brincidofovir (CMV, Pox infections), filociclovir (CMV infections), N-methanocarbathymidine (VZV, HSV infections), and ABI-1968 (HPV infections). Recent representative manuscripts for studies with these drugs and related molecules are shown below.
a. Prichard MN’, Williams JD, Komazin-Meredith G, Khan AR, Price NB, Jefferson GM, et al. Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses. Antimicrob Agents Chemother. 2013;57(8):3518-27. PubMed PMID: 23669381; PubMed Central PMCID: PMC3719742.
b. Beadle JR, Valiaeva N, Yang G, Yu JH, Broker TR, Aldern KA, et al. Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2-Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG),
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a Potent Inhibitor of Transient HPV DNA Amplification. J Med Chem. 2016;59(23):10470-8. PubMed PMID: 27933957.
c. Prichard MN, Kern ER, Hartline CB, Lanier ER, Quenelle DC. CMX001 potentiates the efficacy of acyclovir in herpes simplex virus infections. Antimicrob Agents Chemother. 2011;55(10):4728-34. PubMed PMID: 21788472; PubMed Central PMCID: PMC3186990.
d. James SH, Hartline CB, Harden EA, Driebe EM, Schupp JM, Engelthaler DM, et al. Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. Antimicrob Agents Chemother. 2011:55(10):4682-91. PubMed PMID: 21788463; PubMed Central PMCID: PMC3186952.
2. The second major theme is the study of resistance to antiviral drugs to help understand their mechanism of action and to help manage their use in the clinic.
a. James SH, Price NB, Hartline CB, Lanier ER, Prichard MN*. Selection and Recombinant Phenotyping of a Novel CMX001 and Cidofovir Resistance Mutation in Human Cytomegalovirus. Antimicrob Agents Chemother. 2013;57(7):3321-5. PMID: 23650158; PubMed Central PMCID: PMC3697342; PubMed Central PMCID: PMC3697342.
b. Kimberlin DW, Jester PM, Sanchez PJ, Anmed A, Arav-Boger R, Michaels M, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han J-Y, Palmer A, Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths P, Gutierrez K, Halasa N, Homans J, Shane A, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban |, Kuo H, James SH, Prichard MN, Griffin J, Giles G, Acosta EP, Whitley Ru, for the NIAID Collaborative Antiviral Study Group (CASG). Valganciclovir for Symptomatic Congenital Cytomegalovirus Disease. N. Engl. J. Med. 2015;372(10):933-943.
c. Kimberlin DW, Acosta EP, Prichard MN, Sanchez PJ, Ampofo K, Lang D, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013;207(5):709-20. PubMed PMID: 23230059; PubMed Central PMCID: PMC3563309.
d. Bryan Cu, Prichard MN, Daily S, Jefferson G, Hartline C, Cassady KA, Shimamura M, Hilliard L. Acyclovir-resistant chronic verrucous vaccine strain varicella in a patient with neuroblastoma. Pediatr Infect Dis J. 2008;27(10):946-8. PMID: 18776818.
3. The third major theme has been to help understand the basic biology of human cytomegalovirus as it relates to antiviral therapy. The CMV UL97 kinase was known to phosphorylate ganciclovir, and my research has helped to define its function in viral replication first by demonstrating that it was critical for lytic replication and also that it hyperphosphorylates the retinoblastoma protein, | also showed that the UL114 uracil DNA glycosylase associated with the DNA replication complex and is critical for the replication of DNA, and also helped to show that it also encoded a miRNA important for the control of the host immune response.
a. Prichard MN*, Gao N, Jairath S, Mulamba G, Krosky P, Coen DM, et al. A recombinant human cytomegalovirus with a large deletion in UL97 has a severe replication deficiency. J Virol. 1999;73(7):5663-70. PubMed Central PMCID: PMC112625.
b. Wolf DG, Courcelle CT, Prichard MN, Mocarski ES. Distinct and separate roles for herpesvirus- conserved UL97 kinase in cytomegalovirus DNA synthesis and encapsidation. Proc Natl Acad Sci USA. 2001 ;98(4):1895-900. PubMed Central PMCID: PMG29353.
c. Prichard MN*, Sztul E, Daily SL, Perry AL, Frederick SL, Gill RB, Hartline CB, Streblow DN, Varnum SM, Smith RD, Kern ER. Human cytomegalovirus UL97 kinase activity is required for the hyperphosphorylation of retinoblastoma protein and inhibits the formation of nuclear aggresomes. J Virol. 2008;82(10):5054-67. PubMed Central PMCID: PMC2346732.
d. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, Horwitz E, Prokocimer Z, Prichard MN, Hahn G, Goldman-Wohl D, Greenfield C, Yagel S, Nengle H, Altuvia Y, Margalit H, Mandelboim O. Host immune system gene targeting by a viral miRNA. Science. 2007;317(5836):376-81. PubMed PMID: 17641203.
Complete List of Published Work in MyBibliography https://www.ncbi.nim.nih.gov/sites/mynebi/1 6glk9youY Q55/bibliography/44233567/public/?sort=date&direction =ascending
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D. Additional Information: Research Support and/or Scholastic Performance
Principle Investigator
HHSN272201 100016! (Prichard 1) 6/01/2011 — 5/31/2018 (0%) NIH/NIAID (Base Contract) In Vitro Assessment for Antimicrobial Activity The goals of this contract are to evaluate compounds against the herpesvirus, orthopoxviruses, papillomaviruses and polyomaviruses with in vitro assays. HHSN27200014 (Prichard 2) 9/6/17 — 9/15/18 SE NIH/NIAID Task Order B27 The goals of this contract are to evaluate compounds against the herpesviruses, adenoviruses, polyomaviruses, and papillomaviruses with in vitro assays.
Other Current Support
HHSN272201 100034C (Whitley 1) eee Adaptive sequential study evaluating prevention of neonatal HSV: Detection of maternal shedding at delivery followed by preemptive antiviral therapy in exposed neonates. NIAID, NIH.
HHSN272201 100035C (Whitley 2) Pres A Phase II 6 Weeks Oral Valganciclovir versus Placebo In Infants with Congenital CMV Infection and Hearing Loss. NIAID, NIH.
HHSN272201 100036C (Whitley 3) Safety Tolerability and Pharmacokinetics of CMX-001 in Renal Transplant Recipients with BKV Viremia: A Phase IIA Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study. NIAID, NIH.
HHSN272201 100037C (Whitley 4) A Pharmacokinetic/Pharmacodynamic and Resistance Evaluation of Intravenous Ganciclovir in Premature Infants. NIAID, NIH.
HHSN272201100038C (Whitley 5) Adaptive study of CMX-001 in infants with neonatal herpes simplex virus (HSV). NIAID, NIH.
1U19Al 109680-01 (Whitley 6) eae ah] The goal of the research is to support primary and secondary influenza studies for AD3C Grant. NIAID, NIH.
Completed Research Support
HHSN27200013 (Prichard) 9/16/16— 9/15/17 Task Order B24. Antiviral Screen for herpesviruses, polyomaviruses and papillomavirus.
HHSN27200009 (Prichard 1) 9/30/15- 9/29/16 Task Order B22. Antiviral Screen for herpesviruses, polyomaviruses and papillomavirus.
HHSN27200008 (Prichard 2) 4/1/15 — 9/29/15 Task Order B20. Antiviral Screen for herpesviruses, orthopoxviruses, polyomaviruses and papillomavirus.
HHSN27200007 (Prichard 3) 9/30/14 —9/29/15 Task Order B16. Antiviral Screen for herpesviruses, orthopoxviruses, polyomaviruses and papillomavirus.
HHSN27200005 (Prichard 4) 09/30/13 — 09/29/14 Task Order B12. Antiviral screen for herpesviruses, orthopoxviruses, and polyomaviruses.
HHSN27200004 (Prichard 5) 7/15/12 —11/15/13 NIH - 000 o IP&e 120
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Task Order B14. Antiviral screen for papillomavirus
HHSN27200001 (Prichard 6) 09/17/12 — 09/16/13 Task Order BO9. Antiviral screen for herpesviruses, orthopoxviruses, and polyomaviruses.
HHSN27200002 (Prichard 7) 10/1/11 — 12/31/12 Task Order BO7. Antiviral screen for papillomavirus.
HHSN27200001 (Prichard 8) 10/1/11 — 12/31/12 Task Order B01. Antiviral screen for herpesviruses, orthopoxviruses, and polyomaviruses.
1R43A100401-01A1 (Hilfinger, subcontract) 12/1/12-11/30/14 Broad Spectrum Antiviral Drugs against the DNA Viruses
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BIOGRAPHICAL SKETCH
NAME:
POSITION TITLE: Research Assistant Professor of Pediatrics
RA COMMONS USER NAME:
EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE FIELD OF STUDY
Biology
Entomology Virology
A. Personal Statement
| nave ears ot experience in virology, immunology, and pathogenesis research. My graduate work was focused on defining molecular mechanisms of immunosuppression by Microplitis demolitor Bracovirus. My postdoctoral work and beyond focused on delineating host and viral determinants of reovirus pathogenesis, a tractable model system for studying viral disease. My main goals were to understand the function of innate immune signaling pathways and apoptosis in reovirus neuropathogenesis. Through collaborations with other groups nationally and internationally, | also helped determine the cross-species generalizability of host- pathogen interactions identified in other virus-host systems through collaborations with laboratories around the world. These studies have provided valuable insights into common mechanisms underlying viral dissemination, immune recognition and activation, and interaction with other microbes such as gut microbiota, and their role in viral pathogenesis.
Prior to joining the laboratory of
In this role, | designed and implemented the project management structure for the international network of research laboratories. efforts were instrumental in the launch of three research program:
. In parallel, | served as project manager for five drug-repurposing projects which aimed to find new indications for existing drugs through (oe ae ee RENE with the goal to expedite safe drugs toward IND approval. These experiences have equipped me with widely applicable project management skills and valuable insights into the drug development process.
| will serve as a key personnel for the proposed research. My extensive experience in virology has equipped me with the skills necessary to both perform and provide supervision for the in vitro experiments described in this proposal. In addition, | will apply my project management expertise to facilitate inter- and intra-project interactions, and to track progress and milestones.
B. Positions and Honors
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OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: HOA.OO
eRA COMMONS USER NAME: Og
POSITION TITLE ®@@.@ © HTS Laboratory
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE | Completion (if Date FIELD OF STUDY
INSTITUTION AND LOCATION applicable) | MM/YYYY
OOA,. &) © B.S. © G)A),©) Chemistry & Biology
M.S. Biomedical Science
A. Personal Statement aia
| have ove rears of hands-on laboratory experience, * which includes automation experience, with a large portion involving infectious agent work. | have experience working under both BSL-2 and BSL-3 level containment with an assortment of pathogens and have been responsible for adapting a large number of pathogen-based assays to HTS.
My” "Vvears of hands-on laboratory experience includes basic research with rickettsia, lenti and hanta viruses, usiriy a range of molecular biology, general lab, virology and bacteriology techniques. The scope of these projects ranges from cancer to infectious disease to aging. This experience has allowed me to acquire knowledge and technical skills in many areas to apply to HTS, and how to troubleshoot challenges during adaption of the assay to the automation platform. Over the years | have supervised groups from 5-15 staff members which involved organizing large projects, delegating tasks and coordinating effort for efficient execution. ) G) (A). &) ©)
©) G)).© © | am responsible for the scientific and technical oversight of assay validation plus organizational and logistical support of HTS screening campaigns. | also serve as a PI on the Select Agent Program at SR. | have been responsible for developing the basic strategy for screening in the BSL-2 laboratory with pathogens. This involved testing equipment and protocols, troubleshooting and implementing safety procedures. After successfully conducting a number of HTS campaigns in the BSL-2 laboratory, | worked to adapt these strategies to the BSL-3 environment where we
have successfully screened millions of samples. This ability is my major contribution to programs such as the 0) B) A). ©) ©
which are large multi-center, multi-investigator programs. Based on these successes, |
proposed taking HTS into a BSL-4 environment. As such, | played a key role in the successful collaboration between SR and University of Texas Medical Branch (UTMB) that has succeeded in developing HTS capability
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under BSL-4 level containment. This resulied in two pilot screens of 10,000 compounds done in duplicate, one with Ebola and one with Nipah virus. The results of the Nipah screen has been published’.
| became involved with laboratory automation and robotics when | became
immediately grasped the power and potential of automation to remove throughput limits on scientific progress. | expanded the throughput of the Sequencing Core from 96 samples a day to over 1100 samples per day. | also set up the process for handling large-scale sequencing projects to run efficiently and in a cost-effective manner, providing a valuable resource to researchers at the NIH and FCRDC. Since joining SR in®®**" | have had the opportunity to apply the power of automation and HTS to a large number of drug discovery programs with a high degree of success. My automation background has involved the design and implementation of an automation system for the DNA Sequencing Core at the FCRDC and the design and implementation of two automation platforms at SR. | have been responsible for the selection of laboratory instrumentation and oversight of the integration into automation systems. This includes the design of an automation system within a biocontainment enclosure for use with pathogens in the BSL-2 laboratory.
| have a proven track record of success in the development, validation and implementation of a wide range of scrooning assays with infectious agonts, including viruses, bactoria and yeast. My background in automation, high throughput screening, infectious disease and molecular biology has prepared me to contribute to the success of this project.
B. Positions and Honors
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C. Contribution to Science
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
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Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: OBA. O
eRA COMMONS USER NAME (credential, e.g., agency login): oO@
POSITION TITLE: Research Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE | Completion (if Date FIELD OF STUDY applicable) | MM/YYYY
INSTITUTION AND LOCATION
©) G) A). &) © B.S. ©) G)(A).©) ©) Microbiology/Water Resources Ph.D. Virology Postdoctoral Systems Virology
A. Personal Statement
| have over a decade of experience performing translational research focused on evaluating antiviral therapeutics and elucidating virus and host factor targets for antiviral development. Through my academic and industrial training, | have acquired a broad skillset necessary to help lead this program and meet our milestones. | gained extensive knowledge of coronavirus (CoV) molecular biology, pathogenesis, vaccinoloay, and animal model development within which to evaluate therapeutics through my graduate research at G)@), &) G) (A), (©) (6)
%) 6
. During my graduate career | published extensively on zoonotic CoV and therapeutics ®) G) A). © and the skills gained executing these studies continue to be of use today. Under the guidance of ®)G)).©) © my postdoctoral research focused on the creation of single cell systems within which to better understand the molecular mechanisms guiding hepatitis C virus (HCV) chronic infection. During my tenure at ©G)@).@, | was awarded an NIH F32 fellowship through which | gained the management and leadership skills required to successfully execute grant-guided milestone driven research. To carry out proposed grant aims, | developed a systems virology approach coupling primary human hepatocyte cultures and laser-capture microdissection facilitating the isolation and transcriptional profiling of HCV infected cells at a resolution approaching that of a single cell. These studies yielded a high-impact publication in ©)G) A). &) 6)
Additionally, | was part of team that developed a single molecule RNA fluorescence in situ hybridization (smRNA FISH) technique facilitating the quantitation of HCV RNAs and cellular RNAs associated with the innate immune response in single cells. This RNA FISH technique was applied to help define the mechanism of action (MOA) of several antiviral drugs targeting HCV. After my postdoctoral fellowship, | became an investigator at the OHOA.OO
, | was part of several programs focused on developing and evaluating host targeting small molecules as antivirals. Through this work, | gained expertise in whole genome siRNA screens and triage of hits, antiviral assay development, and design of in vivo efficacy studies. Importantly, | became fluent in the language of preclinical drug development through interactions with experts in drug metabolism, pharmacokinetics, drug safety and toxicology. | ©)G)).&)
develop in vivo imaging technology that facilitated the imaging of virus replication and pulmonary inflammation in live animals. Not only did this program result in a publication on in vivo imaging techniques for influenza
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virus, but | also gained expertise in managing research collaborations between academia and industry which continues to be of great value.
. The current application builds upon this work as we explore the development of new antivirals targeting CoV and new modalities for treatment.
B. Positions and Honors
C. Contributing to Science
Contact PD/PI: WHITLEY, RICHARD J.
Complete List of Published Work in NCBI MyBibliography:
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D. Research Support
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OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
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NAME: Pei-Yong Shi
RA COMMONS USER NAME (credential, e.g., agency locin): OO
POSITION TITLE: I.H. Kempner Professor of Human Genetics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION fi eae ) completion Date FIELD OF STUDY Nanjing Normal University, China B.S. 06/1989 Biology Georgia State University, Atlanta, GA Ph.D. 12/1995 Virology Yale University School of Medicine, New Haven, CT Postdoc 1998 Biochemistry
A. Personal Statement
| have been working on flavivirus replication, antiviral drug discovery, and vaccine research for 27 years. My unique experience in public health laboratory (Wadsworth Center, New York State Department of Health; 8 years), pharmaceutical companies (Novartis and Bristol-Myers Squibb; total 10 years), and academia (University of Texas Medical Branch, Yale, and other universities; total 9 years) allows our work to focus on the interface between basic and translational research. Our basic research illuminates the mechanism of viral replication that could be utilized for the development of novel diagnosis, antiviral, and vaccine. In return, our translational research provides unique tools and systems to discover the molecular mechanism of viral replication. | have published over 230 peer-reviewed papers in the leading journals for virology, including Nature, Science, Cell, PNAS, Host Cell & Microbe, and PLoS Pathogen. Our work has generated bodies of knowledge that have significantly advanced our understanding of flavivirus replication, diagnostics, drug discovery, and vaccine development. Besides academic excellence, | also have a strong track record of senior leadership role at leading pharmaceutical company (e.g., Executive Director at Novartis Institute for Tropical Diseases) where | set up antiviral strategies and executed drug discovery and development. | aspire to integrate my expertise in academia, industry, and government to advance basic and translational research. This is exemplified by our recent work on Zika virus: We established the first reverse genetic system for the virus, developed a single-shot live- attenuated vaccine candidate, developed rapid diagnostic assays currently under FDA approval, and identified genetic changes that may contribute to the recent explosion of Zika epidemics.
e Shan, C., Xie, X., Muruato, A.E.,, Rossi, S.L., Roundy, C.M., Azar, S.R., Yang, Y., Tesh, R.B., Bourne, N., Barrett, A.D., Vasilakis, N., Weaver, S.C.,and Shi, P.-Y. 2016. An infectious cDNA clone of Zika virus to study viral virulence, mosquito transmission, and antiviral inhibitors. Cell Host & Microbe. 19(6):891-900
e Shan,C., Muruato, A.E., Nunes, B.T.D., Luo, H., Xie, X., Medeiros, D.B.A., Wakamiya, M., Tesh, R.B., Barrett, A.D., Wang, Tian W., Weaver, S.C., Vasconcedos, P.F.C., Rossi, S.L., Shi, P.-Y. 2017. A live-attenuated Zika virus vaccine candidate induces sterilizing immunity in mouse models. Nature Med. 23(6):763-767.
e Shan, C., Muruato A.E., Jagger, B.W., Richner, J., Nunes, B.T.D., Medeiros, D.B.A., Xie, X., Nunes, J.G.C., Morabito, K.M., Kong, W.P., Pierson, T.C., Barrett, A.D., Weaver, S.C., Rossi, S.L., Vasconcelos, P.F.C., Graham, B.S., Diamond, M.S., Shi, P.-Y. 2017. A single-dose live-attenuated vaccine prevents Zika virus infection, pregnancy transmission, and testis damage. Nature Comm. doi: 10.1038/s41467-017-00737-8.
e Xia, H., Luo, H., Shan, C., Muruato, A.E., Nunes, B.T.D., Medeiros, D.B.A., Zou, J., Xie, X., Giraldo, M.l., Vasconcelos, P.F.C., Weaver, S.C., Wang, T., Rajsbaum, R., Shi, P.-Y. 2018. An evolutionary NS1 mutation enhances Zika virus evasion of host interieron induction. Nature Comm. Jan 29;9(1):414. doi: 10.1038/s41467-017-02816-2.
In this application, | will work with a cohesively integrated multidisciplinary team from academia and industry to develop flavivirus therapeutics. We will deliver the proposed milestones by combining the cutting-edge biology from academia and drug discovery acumen from industry.
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B. Positions and Honors
1996-1998 Postdoctoral associate, Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT.
1998-2000 Research Scientist, Department of Infectious Disease, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT.
2000-2008 = Research Scientist (equivalent to Full Professor with tenure), Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY.
2008-2010 Senior Unit Head — Dengue, Novartis Institute for Tropical Diseases, Singapore
2008- Adjunct Full Professor, Emerging Infectious Disease Center, Duke-National University of Singapore, Graduate Medical School, Singapore
2011-2015 Executive Director, Disease Biology Unit, Novartis Institute for Tropical Diseases, Singapore
2015- |.H. Kempner Professor of Human Genetics, Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX
2016 - Vice Chair for Innovation and Commercialization, Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX
2012- Scientific Advisory Board, BIO Ventures for Global Health (BVGH)
2007- Editorial Board, Virology
2009- Editorial Board, Journal of Virology
2010-2016 Editor, Journal of General Virology
2014- Associate Editor, ACS Infectious Diseases
2015- Editorial Board, Antiviral Research
2015 Guest Editor, Symposium for Flavivirus Drug Discovery, Antiviral Research
2016- Associate Editor, Vaccine, Nature Publishing Group
2018- Fellow, American Academy of Microbiology
C. Contribution to Science
1. West Nile virus. In response to the outbreak of West Nile virus in New York City in 1999, my group developed (i) a robot-based high-throughput diagnostic method for viral RNA extraction and detection which was routinely used by public health laboratories for virus surveillance; (ii) a proprietary technology for serologic diagnosis that can differentiate between West Nile virus infection and other flavivirus infections in humans (Wong et al (2003) J. Clin. Microbiol.); (iii) the first CDNA infectious clone of the epidemic New York strain of West Nile virus (Shi et al (2002) JY. Virol.); (iv) the first luciferase replicon system of flavivirus that can differentiate between viral RNA translation and RNA synthesis (Lo et al (2003a) J. Virol); (v) a replicon-containing cell line and luciferase reporter virus that could be used for high-throughput drug screening (Lo et al (2003b) uJ. Virol); (vi) novel inhibitors of West Nile virus. The technologies for serologic diagnosis and drug screening were awarded with US patents, and have been licensed to a number of commercial companies. In addition, we have identified viral RNA elements that are critical for West Nile virus replication. Our research has significantly impacted on West Nile virus diagnosis, viral replication and pathogenesis, and antiviral discovery.
e Wong, S.J, Boyle, R.H., Demarest, V.L., Woodmansee, A.N., Kramer, L.D., Li, H., Drebot, M., Koski, R.A., Fikrig, E., Martin, D.A., and Shi, P.-Y. 2003. An immunoassay targeting nonstructural protein 5 to differentiate West Nile virus infection from dengue and St. Louis encephalitis virus infections, and flavivirus vaccination. J. Clin. Microbiol. 41, 4217-23.
e Shi, P.-Y., Tilgner, M., Lo, M.K., Kent, K.A. and Bernard, K.A. 2002. An infectious cDNA clone of the epidemic West Nile virus from New York City. J. Virol. 76, 5847-56.
e Lo, M.K., Tilgner, M., Bernard, K.A., and Shi, P.-Y. 2003a. Functional analysis of mosquito-borne flavivirus conserved sequence elements within 3’ untranslated region of West Nile virus using a reporting replicon that differentiates between viral translation and RNA replication. J. Virol. 77, 10004-14.
e Lo, M.K., Tilgner, M., and Shi, P.-Y. 2003b. A potential high-throughput assay for screening inhibitors of West Nile virus replication. J. Virol. 77, 12901-6.
2. Flavivirus RNA methylation. Our group discovered that flavivirus NSS protein catalyzes RNA cap methylation (Ray et al (2006) J. Virol.) as well as genomic RNA internal methylation (Dong et al (2012). PLoS Pathogen). |n collaboration with Dr. Hongmin Li, we solved the crystal structure of West Nile virus methytransferase. Mechanistically, we demonstrated that flavivirus NS5 catalyzes N-7 and 2'-O cap methylations in a sequential manner through a substrate repositioning model (Dong et al (2008) J. Virol.). The order of the two cap methylation events is controlled by substrate preference. Unlike host methyltransferase which methylates RNA cap without specific RNA sequence, flavivirus methyltransferase requires distinct viral RNA
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elements for its cap methylation reactions (Dong et al (2007) J. Virol.). Such substrate specificity supports the possibility to design inhibitors that specifically block viral methyltransferase without affecting the host enzyme.
e Ray, D., Shah, A., Tilgner, M., Guo,Y., Zhao, Y., Dong, H., Deas, T.S., Zhou, Y., Li, H., and Shi, P.-Y. 2006. West Nile virus 5’-Cap structure is formed by sequential guanine N-7 and ribose 2’-O methylations by nonstructural protein 5. J. Virol. 80, 8362-70.
e Dong, H., Chang, D.C., Hua, M.H.C., Lim, S.P., Chionh, Y.H., Hia, F., Lee, Y.H, Kukkaro, P., Lok, S.-M., Dedon, P.C., and Shi, P.-Y. 2012. 2’-O methylation of internal adenosine by flavivirus NS5 methyltransferase. PLoS Pathogens. 8(4), e1002642.
e Dong, H., Ren, S., Zhang, B., Zhou, Y., Puig-Basagoiti, F., Li, H., and Shi, P.-Y. 2008. West Nile virus methyltransferase catalyzes two methylations of the viral RNA cap through a substrate repositioning mechanism. J. Virol. 82, 4295-407.
e Dong, H., Ray, D., Ren, S., Zhang, B., Puig-Basagoiti, F., Takagi, Y., Ho, C.K. Li, H., and Shi, P.-Y. 2007. Distinct RNA elements confer specificity to flavivirus RNA cap methylation events. J. Virol. 81, 4412-21.
3. Function of 2’-O methylation and vaccine. In collaboration with Michael Diamond, we uncovered, for the first time, that 2'-O cap methylation functions to evade innate immune response (Daffis et al (2010) Nature). Viral RNA containing 2'-O cap methylation mimics host MRNA to evade host immune restriction. This discovery led to the invention of a proprietary technology that uses methyltransferase-defective virus for vaccine development. Our studies using animal models (mice and non-human primates) have demonstrated that such mutant viruses are potent vaccine candidates for West Nile virus (Zhou et al (2007) J. Virol.), Japanese encephalitis virus (Li et al (2011) v. Virol.), and dengue virus (Ztst et al (2012). PLoS Pathogen). Subsequently, the methyltransferase- based vaccine approach was also successfully reproduced in other RNA viruses (e.g., coronavirus) by other groups, demonstrating a wide application of this novel vaccine approach. Collectively, these results exemplify how cutting-edge basic research could lead to novel approaches for translational research.
¢ Daffis, S., Szretter, K.J., Schriewer, J., Schneller, S., Zust, R., Dong, H., Thiel, V., Buller, R.M., Gale, M.J, Shi, P.-Y., and Diamond, M.S. 2010. 2’O methylation of the viral mRNA cap evades intrinsic host restriction by IFIT family members. Nature 468(7322), 452-56.
e Zhou, Y., Ray, D., Zhao, Y., Dong, H., Ren S., Li, Z., Guo, Y., Bernard, K.A., Shi, P.-Y., and Li, H. 2007. Structure and function of flavivirus NS5 methyltransferase. J. Virol. 3891-903.
e Li, S.-H., Dong, H.-P., Li, X.-F., Xie, X., Zhao, H., Deng, Y.-Q., Wang, X.-Y., Ye, Q., Zhu, S.-Y., Wang, H.-J., Zhang, B., Qin, E.-D., Qin, C.-F., and Shi, P.-Y. 2013. Rational design of a flavivirus vaccine through abolishing viral RNA 2' -O methylation. J. Virol. 87(10):5812-9.
e Ziust, R., Dong, H., Li, X.-F., Chang, D.C., Zhang, B., Jiang, T., Li, S.-H., Deng, Y.-Q., Ellis, B.R., Ellis, E.M., Qin, C-F., Shi, P.-Y., Fink, K. 2013. Rational design of a live attenuated dengue vaccine: 2’-O- methyltransferase mutants are highly attenuated and immunogenic in mice and macaques. PLoS Pathogens. 9(8):e1003521
4. Dengue virus replication and virion assembly. Our work on dengue virus replication has focused on the molecular interaction within viral replication complex. We have identified that (i) dengue virus NS4B protein interacts with NS3 (Zou et al (2015a) J. Virol.); (ii) the NS4B also interacts with vrial NS4A protein (Zou et al (2015b) J. Virol.); (iii) the NS4A protein oligomerizes (Lee et al (2015) J. Virol.). We also determined the membrane topology of NS2A protein and demonstrated that distinct NS2A molecules are responsible for dengue virus RNA synthesis and virion assembly (Xie et al (2015) J. Virol.). In collaborations with Drs. Julien Lescar and Dahai Lo, we solved the crystal structures of dengue virus NS5 protein alone and in complex of viral RNA substrate. The results on flavivirus NS4B biology have set a solid foundation for preclinical studies of our NS4B inhibitors.
e Zou, J., Lee, L.T., Yin, W.-Q., Xie, X., Lu, S., Yau, Y.H., Shochat, S.G., Kang, C., Lescar, J., and Shi, P.-Y. 2015a. Mapping the interactions between the NS4B and NS3 proteins of dengue virus. J. Virol. 89(7):3471- 83.
e Zou, J., Xie, X., Wang, Q.-Y., Dong, H, Lee, M.Y., , Z., Shochat, S.G., Kang, C., Yuan, Z., and Shi, P.-Y. 2015b. Characterization of dengue virus NS4A and NS4B protein interaction. J. Virol. 89(7):3455-70.
e Lee, C.M., Xie, X., Zou, J., Dong, H., and Shi, P.-Y. 2015. Determinants of dengue virus NS4A protein oligomerization J. Virol. 89(12):6171-83.
e Xie, X., Zou, J., Puttiknunt, C., Yuan, Z., and Shi, P.-Y. 2015. Two distinct sets of NS2A molecules are responsible for dengue virus RNA synthesis and virion assembly. J. Virol. 89(2):1298-313.
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5. Flavivirus drug discovery. We have pioneered flavivirus drug discovery by pursuing four antiviral strategies. Each strategy has identified promising inhibitors of dengue virus. (i) High-throughput screening (HTS) using viral infection assays (Wang et al (2011) J. Virol.). (ii) HTS using viral enzyme assays (Chen et al (2010) J. Virol.). (iii) structure-based rational design (Lim et al. (2011) J. Biol. Chem.). (iv) Nucleoside/ nucleotide analog inhibitors (Yin et al (2009) PNAS). Many of our publications were highlighted by leading journals in drug discover such as Nature Reviews Drug Discover. Some of our compounds, such as NITD-008 (an adenosine nucleoside analog), have become standard tool compounds in the field of antiviral drug discovery.
e Wang, Q.-Y., Bushell, S., Qing, M., Xu, H.¥., Bonavia, A., Nunes, S., Zhou, J., Poh, M. K., Florez de Sessions, P., Niyomrattanakit, P., Dong, H., Hoffmaster, K., Goh, A., Nilar, S., Schul, W., Jones, S., Kramer, L., Compton, T., and Shi, P.-Y. 2011. Inhibition of dengue virus through suppression of host pyrimidine biosynthesis. J. Virol. 85(13), 6548-56.
e Chen, Y.-L., Niyomrattanakit, P., Dong, H., Yin, Z., Qing, M., J. Glickman, F., Lin, K., Mueller, Hans Voshol, D., Lim, J.Y.H., Vasudevan, S.G., Keller, T.H., and Shi, P.-Y. 2010. Inhibition of dengue virus polymerase though blocking the RNA tunnel. J. Virol. 84(11), 5678-86.
e Lim, S.P., Sonntag, S., Noble, C., Nilar, S.H., Ng, R.H., Zou, G., Monaghan, P., Dong, H., Lui, B., Chung, K.Y., Lee, G., Ding, M., Chan, W.L., Wang, G., Yap L.J., Chao, A.T., Lescar, J., Yin Z., TR V., Keller, T.H., and Shi, P.-Y. 2011. Small-molecule inhibitors that selectively block dengue virus methyltransferase. J. Biol. Chem. 286(8), 6233-40.
e Yin, Z., Chen, Y.-L., Schul, W., Wang, Q.-Y., Gu, F., Duraiswamy, J., Reddy, K.R., Niyomrattanakit, P., Lakshminarayana, S.B., Goh, A., Xu, H.Y., Liu, W., Liu, B., Lim, J.Y.H., Ng, C.Y., Qing, M., Lim, C.C., Yip, A., Wang, G., Chan, W.L., Tan, H.P., Lin, K., Zhang, B., Zou, G., Bernard, K.A., Garrett, C., Beltz,B., Dong, M., Weaver. M., He, H., Han, X., Pichota. A., Dartois, V., Keller, T.H., and Shi, P.-Y. 2009. An adenosine nucleoside inhibitor of dengue virus. PNAS 106(48), 20435-9.
Complete list of published works in MyBibliography https://www.ncbi.nim.nih.gov/myncbi/collections/mybibliography/?reload=deleteSuccess&dnum=1
D. Research Support
Ongoing research su rt i pa OOO
PI: Milan Chheda, Washington University; Co-PI: Michael Diamond, Washington University Role: Co-Pl/M@effort; total $100,000)
Using Zika virus to treat glioblastoma
The award is to develop Zika virus for therepy of human glioblastoma.
The University of Texas Medical Branch: Technology Commercialization Program Award Role: P! (No salary effort; total $50,000) 01/04/17-01/03/18 Co-PI: Ping Ren
Dengue and Zika serologic diagnosis
The award is to develop reporter dengue viruses of all four serotypes for serologic test.
RO1A1127744-01A1 Supplement 06/01/17- 05/31/22 NIH/NIAID
PI: Tian Wan
Role: Co-PI Wetton total $500,000)
Development of live-attenuated Zika
This supplement award aims to develop a |ve-attenuated vaccine for Zika virus
R2106 09/01/17- 08/31/19
NIH/NIAID
PI: Ricardo Rajsbaum
Role: Collaborator © effort; total $50,000)
Ubiquitination of Zika virus proteins
The goal of this project to study ubiquitination of Zika virus proteins and their function in viral replication and immune response
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CDC U01CK0000512 12/31/16-12/29/21
Western Gulf Center of Excellence for Vector-Borne Diseases
Role: Project Leader ®@effort; total $120,000 per year)
Pl: Scott Weaver
My project is to develop innovative, high-throughput multiplex neutralization assay for arbovirus diagnosis
06/01/17-7/31/18 ‘ole: fort; total A The award is to develop a rapid Zika diagnostic assay - Reporter Zika virus assay for clinical use and obtain
US FDA Emergency Use Authorization.
UTMB Clinical and Translational Sciences Awari TR-001439 12/20/16-12/19/18 Role: Lead Investigator on vaccine development glo: total direct cost $44,000)
PI: Allan Brasier
This award is to promote UTMB's multidisciplinary translational research and education at UTMB.
Cooperate Rosoarch 01/10/16-07/31/18 Role: PI (@@effort; total A
Development of antiviral drugs for dengue and Zika viruses This grant aims to collaborate with (0 develop antiviral therapeutics.
Brazil Ministry of Health Role: P| total $1,950,000) 04/15/16-04/14/18 Development of Zika virus vaccine The project is to develop Zika virus vaccine.
The University of Texas System STARS Program Award 10/15/15-10/14/18
Role: P! (No percentage effort needed; total $1,000,000)
The award is to attract and retain the best-qualified faculty to the University of Texas System. The fund is used for laboratory renovation and capital equipment procurement.
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BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME:
eRA COMMONS USER NAME (credential, e.9., agency login) NS POSITION TITLE: Research Associate Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion
(if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) | MM/YYYY
B.S. See ® Molecular Biology Ph.D. Microbiology & Immuno Postdoctoral RNA/Protein Interaction Postdoctoral Virology
A. Personal Statement
The identification of highly pathogenic human coronaviruses (SARS-CoV and MERS-CoV) underscored the importance of understanding how viruses emerge from zoonotic reservoirs and how these emergent viruses replicate and cause pathogenesis in the new host. My research has focused on several key aspects of these questions by working to understand the cellular tropism of SARS-CoV and MERS-CoV in primary human lung cells, how host genetic pathways and gene networks affect virus replication and pathogenesis and how
manipulating the coronavirus genome changes the host innate immune response to virus infection. Over the past four years | have worked as per of a team of virologists from eae to
determine the efficacy of a range of compound against highly pathogenic human coronaviruses and pre- epidemic coronavirus strains. Each set of collaborations has already established communication channels via email and conference calls and our work with
Our work with is providing critical data for a potential IND application and we have confirmed that are efficacious against SARS-CoV and will provide the basis for prodrug
studies.
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B. Positions and Honors
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OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: Streblow, Daniel N., Ph.D.
eRA COMMONS USER NAME (credential, e.g., agency login) | RAS
POSITION TITLE: Associate Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
Completion DEGREE fer Date FIELD OF STUDY INSTITUTION AND LOCATION (if applicable) MM/YYYY University of Wisconsin, Madison, WI BS 05/92 Pharmacology University of Wisconsin, Madison, WI PhD 08/97 Viral Pathogenesis Oregon Health & Science University, Portland, OR Postdoc 12/01
A. Personal Statement
My undergraduate training was in pharmacology/toxicology at the University of Wisconsin-Madison. During graduate school | studied HIV pathogenesis doing work that involved both utilizing molecular and whole animal (rhesus macaque) models. During my post-doctoral training | shifted my focus to the large DNA virus, human cytomegalovirus (CMV). My lab has developed a number of in vitro and in vivo models to determine the mechanisms of CMV-accelerated allograft rejection. In addition, we have been involved in the development of CMV vaccine vectors in rhesus-CMV. My laboratory, in collaboration with Drs. Mike Axthelm and Messaoudi, generated a rhesus macaque chikungunya virus (CHIKV) infection anima! model to identify age-related defects in the response to CHIKV infection. We have utilized this model to characterize CHIKV infection in NHP and define the immune responses to the virus infection and efficacy test therapeutic antibodies against CHIKV. We have developed protocols and reagents for the identification and quantification of virus, disease assessments as well as to characterize both innate and adaptive (T and B cell) responses directed against CHIKV in mice and NHP. For the past 5 years, in collaboration with Southern Research my lab has worked closely with the laboratories of Drs. Heise, Morrison and DeFilippis to identify small molecule inhibitors of VEEV and CHIKV and to characterize their antiviral activity and mode of action. We have performed extensive SAR for a number of the lead compounds; and for the purposes of this U19 application, we will continue our collaborative efforts to further characterize our lead compounds, optimize their activity, solubility and stability. We will then efficacy test these optimized lead compounds in our extensive collection of alphavirus animal models.
B. Positions and Honors
Positions and Employment
1997-2001 Postdoctoral Fellow, Oregon Health Sciences University, Portland, OR
2001-2003 Research Assistant Professor, Department of Molecular Microbiology & Immunology, Oregon Health Sciences University, Portland, OR
2003-2013 Assistant Professor, Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR
2006-Present Instructor, Oregon Health & Science University, Portland, OR
2007-Present Faculty Member, Division of Pathobiology & Immunology, Oregon National Primate Research
Center 2013-Present Associate Professor, Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR
Professional Activities 2007-Present Editorial Board Member, Journal of Virology 2010-Present NIH Peer Review Committee, NIAID, ad hoc reviewer
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2010-Present Welcome Trust-Intermediate Level Biology Grants, ad hoc reviewer
2009-2015 = PNWRCE National Small Molecule Screening Library for the Biodefense RCEs, review board Honors
1991-1992 ‘Hilldale Fellowship’ at the University of Wisconsin, Madison, WI
1995-1996 ‘Cremer Scholar Award,’ Dept. of Pathology, University of Wisconsin, Madison, WI 1997-2001 Postdoctoral Fellowship, Oregon Health Sciences University, Portland, OR
2000 Oregon Health & Science University Postdoctoral Paper of the Year
C. Contribution to Science 1. Development of a Non-human Primate Model of CHIKV Infection and Disease. CHIKV is a NIAID Category C Biodefense priority mosquito-transmitted Alphavirus that causes a febrile, sometimes-fatal disease that involves incapacitating myalgia and arthralgia that can persist for years. FDA approved anti-CHIKV therapeutics and vaccines are currently not available. Therefore, in order to reduce the impact of this virus and devastating arthralgia that it causes, we must develop new therapies and vaccines to treat persistent CHIKV infections. We have developed a non-human primate model that parallels CHIKV infection and disease in humans; and we are characterizing CHIKV infection and antiviral immunity in this model using both adult and aged Rhesus monkeys. Using our NHP-CHIKV infection model, we have demonstrated that aged animals exhibit higher susceptibility to persistent CHIKV infection as a result of defects in the development of T cell responses directed against the virus. A safe and effective vaccine that can protect vulnerable populations from CHIKV infection is clearly warranted. In addition, we are currently determining whether there exist differences in joint disease, viral load, distribution and/or immune infiltrates between CHIKV infected adult and aged animals at early times post infection in an effort to lay the foundation for the design of successful vaccine strategies to prevent CHIKV-associated morbidities in vulnerable populations. Lastly, we have tested the efficacy of neutralizing antibody therapy has on pre-existing CHIKV infection of NHP joint tissues. This model will be extremely useful for the pre-clinical efficacy testing of antiviral therapies and vaccines directed against CHIKV. | served as primary or co-investigator for these studies:
1. Messaoudi I, Vomaske J, Totonchy T, Kreklywich CN, Haberthur K, Springgay L, Brien JD, Diamond MS, Defilippis VR, and Streblow DN. Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity. PLoS Negl Trop Dis. 2013 Jul 25;7(7):e2343. PMCID: PMC3723534
2. P Pal, Hawman DW, Huang YJ, Messaoudi |, Kreklywich C, Denton M, Legasse AW, Smith PP, Johnson S, Axthelm MK, Vanlandingham DL, Streblow DN, Higgs S, Morrison TE and Diamond MS. Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. Journal of Virology. 2014 Aug:88(15)8213-26. PMCID: PMC4135940
3. Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques. Broeckel R, Fox JM, Haese N, Kreklywich CN, Sukulpovi- Petty S, Legasse A, Smith PP, Denton M, Corvey C, Krishnan S, Colgin LMA, Ducore RM, Lewis AD, Axthelm MK, Mandron M, Cortez P, Rothblatt J, Rao E, Focken |, Carter K, Sapparapau G, Crowe JE Jr, Diamond MS,StreblowDN. PLoS Neg! Trop Dis. 2017 Jun 19;11(6):e0005637. doi: 10.1371 /journal.pntd.0005637. eCollection 2017 Jun. PMID: 28628616 PMCID: PMC5491320
2. Development of a Non-human Primate Model of Zika Virus Infection and Disease.
Zika virus (ZIKV) is an emerging Flavivirus that spread explosively through the Western hemisphere in 2014- 2016. Infection has been associated with dengue-like symptoms, including fever, rash, arthralgia, and conjunctivitis, and has also been associated with auto-immune/ neurological sequelae such as Guillain-Barré syndrome. The most significant finding to date is that ZIKV infection of pregnant women has been associated microcephaly, other developmental abnormalities or death of the fetus. We have developed a rhesus macaque model of ZIKV infection in pregnant and non-pregnant rhesus macaques and characterized clinical features, viral replication, tropism, and immune response. Following subcutaneous infection, animals developed transient viremia from 1-6 dpi and viruria from 2-7 dpi that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. Virus tropism within infected animals was detected and persisted in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals.
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika
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Syndrome (CZS). We infected pregnant rhesus macaques at three different gestational age time points and investigated the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies revealed dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi, and evidence of altered fetal brain development and relative small size but in the absence of overt microcephaly compared to gestational age-matched controls. The novel observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This clinically relevant translational model of persistent ZIKV infection during pregnancy reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development, which will be investigated in this proposal.
1. Hirsch AJ, Smith JL, Haese NN, Broeckel RM, Parkins CJ, Kreklywich C, DeFilippis VR, Denton M, Smith PP, Messer WB, Colgin LM, Ducore RM, Grigsby PL, Hennebold JD, Swanson T, Legasse AW, Axthelm MK, MacAllister R, Wiley CA, Nelson JA, and Streblow DN. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog. 2017 Mar 9;13(3):e1006219. PMCID: PMC5344528
2. Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Hirsch AJ, Roberts VHJ, Grigsby PL, Haese N, Schabel MC, Wang X, Lo JO, Liu Z, Kroenke CD, Smith JL, Kelleher M, Broeckel R, Kreklywich CN, Parkins CJ, Denton M, Smith P, DeFilippis V, Messer W, Nelson JA, Hennebold JD, Grafe M, Colgin L, Lewis A, Ducore R, Swanson T, Legasse AW, Axthelm MK, MacAllister R, Moses AV, Morgan TK, Frias AE, Streblow DN. Nature Commun. 2018 Jan 17;9(1):263. doi: 10.1038/s41467-017-02499-9. PMID: 29343712, PMCID: PMC5772047
3. Characterization of the Role of Cytomegalovirus in the Development of Vascular Disease and
Chronic Allograft Rejection.
We are studying the role of human cytomegalovirus (HCMV) in the development of chronic diseases including
vascular disease and chronic rejection (CR) of solid organ transplants. The precise role of CMV in these
diseases is still uncharacterized, and as such my lab has been studying the mechanisms of HCMV-accelerated vascular disease through: 1) identification of viral and cellular genes expressed during these diseases and
determining their function using in vitro and in vivo models of CMV-accelerated vascular disease; 2)
determination of the immunological mechanisms of viral acceleration of chronic allograft rejection from latently
infected donors, which is the most common cause of HCMV-associated disease in transplant patients; 3)
determination of the function of CMV-encoded chemokines and chemokine receptors; and 4) generation of
vaccine strategies to prevent CMV reactivation and disease in transplant patients.
1. DN Streblow, CN Kreklywich, Q Yin, VT De La Melena, JW Cook, Corless, CL, Vink,C, Bruggeman, CA, Nelson JA, SL Orloff. Upregulation Of Chemokine Expression Correlates With The Development Of Cytomegalovirus-Accelerated Chronic Rejection In Rat Heart Transplants. J Virol, February 2003; 77(8):2182-2194. PMCID: PMC140920.
2 DN Streblow, CN Kreklywich, T Andoh, AV Moses, J Dumortier, PP Smith, V Defilippis, K Fruh, JA Nelson, and SL Orloff. 2008. The Role of Angiogenic and Wound Repair Factors During CMV-Accelerated Transplant Vascular Sclerosis in Rat Cardiac Transplants. Amer J Transplant. Feb;8(2):277-87. PMID: 18093265.
3. Orloff SL, Hwee YK, Kreklywich CN, Andoh TF, Hart E, Smith P, Messaoudi | and Streblow DN. Cytomegalovirus Latency Promotes Cardiac Lymphoid Neogenesis and Accelerated Allograft Rejection in CMV Naive Recipients. Amer Journal of Transpl. 2011 Jan;11(1):45-55. PMCID: PMC3454525
4. DN Streblow, Hwee YK, Kreklywich CN, Ando T, Denton M, Smith P, Hart E, Broekel R, Pallett C, Rogers K, Streblow AD, Chuop M, Perry A, Slifka M, Messaoudi |, and Orloff SL. Rat cytomegalovirus vaccine prevents acclerated chronic rejection in CMV-naive recipients of infected donor allograft hearts. Amer J Transplant. 2015 July:15(7):1805-16. PMCID: PMC5006870
5. DN Streblow, KW van Cleef, CN Kreklywich, C Meyer, P Smith, V Defilippis, F Grey, K Fruh, R Searles, C Bruggeman, C Vink, JA Nelson, SL Orloff. 2007 Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. Journal of Virology. Apr:81(8):3816-26. PMCID: PMC1866122.
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6. CC Baca Jones, CN Kreklywich, | Messaoudi, J Vomaske, E McCartney, SL Orloff, JA Nelson and DN Streblow. 2009. Rat Cytomegalovirus Infection Depletes MHC | and II in Bone Marrow Derived Dendritic Cells. Virol 2009 May 25;388(1):78-90. PMCID: PMC2749604.
7. Meyer C, Grey F, Kreklywich CN, Andoh TF, Tirabassi RS, Orloff SL and Streblow DN. Cytomegalovirus miRNA expression is tissue specific and associated with persistence. Journal of Virology. 2011 Jan;85(1):378-89. PMCID: PMC3014154
Complete List of Published Work in MyBibliography: http://www.ncbi.nim.nih.gov/sites/myncbi/daniel.streblow.1/bibliography/41163876/public/?sort=date&d
irection=ascending D. Research Support
Ongoing Research Support
5 RO1 Al116633-02 Streblow (PI) 03/01/2016 — 02/28/2021
NIH/NIAID
Characterizing the Role of CMV Latency in Solid Organ Transplant Rejection
The main goal of this project is to determine the mechanisms of cytomegalovirus-mediated solid organ transplant rejection. Role: Pl
5 U19 Al109680-04 Whitley (PI) 03/01/2014 — 02/28/2019
NIH/NIAID
Antiviral Drug Discovery and Development Center: Project 3: Novel Therapeutic Strategies Targeting Re- emerging Alphaviruses
The main goal of this project is to develop novel nucleoside and nucleotide inhibitors directed against Alphaviruses including Chikungunya virus and Venezuelan Equine Encephalitis virus, Role: Project 3 Leader
POO pier (P|) 07/28/2014 — 08/31/2020
Development of Attenuated CMV Vectors for an HIV/AIDS Vaccine
The overall goal of this project is the development of an HCMV vector-based HIV/AIDS vaccine (composed of one or more HIV insert-expressing HCMV vectors) that is optimized for safety, efficacy and manufacturability. Role: Project Leader, Activity 2.3
1 U19 Al128741-01 (Picker) 03/02/2017 — 02/28/2022
NIH/NIAID
Development of Immunogenicity- and Efficacy-Optimized CMV Vectors for an HIV/AIDS Vaccine: Project 4: Optimization of CMV Vector CD8+ T Cell Response Programming by Modification of CMV-Encoded Molecular Mechanisms That Interfere with Unconventional CD8+ T Cell Response Priming
In Project 4 we first seek to identify the specific motifs in the UL128 and UL130 proteins which block MHC-E- restricted CD8+ T cell priming with the goal of mutating these regions to abrogate their MHC-E-response inhibition while retaining PRC function. Utilizing a deletion strategy we will ascertain whether any non-essential HCMV genes have this activity. Finally, utilizing the data from Projects 2-4, Project 4 will construct the 2nd generation “response and safety” optimized HCMV/HIV vector for manufacture and clinical testing in Project 5. Role: Pl, Project 4
1 P01 Al127335-01 (Nelson/Yurochko) 08/15/2017 — 07/31/2022
NIH/NIAID
Human Cytomegalovirus Dysregulation of Host Hematopoietic Progenitor Cell Signaling Pathways to Modulate Latency, Reactivation and Hematopoiesis during Transplantation: Project 3: HCMV US28 regulation of host cell signaling in viral latency and hematopoiesis
In this project we will examine UL7 signaling in CD34+ HPCs and identify the cellular pathways necessary for viral reactivation and hematopoiesis in the context of infection. We will also determine whether these UL7 pathways cross-talk with pathways modulated by UL133/8 (Project 1), HCMV miRNAs (Project 2), US28 (Project 3) and wild-type HCMV infection (Project 5).
Role: Project Leader, Project 3
5 R21 HD091032-02 (Streblow) 09/20/2016 — 8/31/2018
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Development of a NHP Model for Determining the Causal Relationship between Zika Virus Infection during Pregnancy and Fetal Microcephaly The goal of this project is to develop a NHP model of Zika virus infection and fetal disease. Role: PI
SRA-16-131 oo" 12/14/2016 — 12/13/2017 iological Protiling of Anti-CHIKV Recombinant mAbs
The major goal of this project is to determine the efficacy of mAb’s directed against CHIKV using in vitro and mouse models. Role: Pl
DARPA-BAA-16-33 (Streblow) 08/29/2017 — 08/28/2018 ARPA
Anti-CHIKV mAb Therapeutics
The goal of the project is to characterize a novel immunotherapeutic directed against CHIKV in NHP.
Role: P|
Completed Research Support Picker (P!) 09/22/2014 — 09/30/2017
MHC II- and MHC E-restricted CD8+ T Cells and Control of HIV The goal of this project is to provide fundamental research on a new type of vaccine-elicited CD8+ T cell immunity with the potential to control and clear HIV. Role: Project Manager; Outcome 8 Activity 4.3
5 P50 CA097186-12 Streblow (PI) 06/01/2015 — 05/31/2016
Fred Hutchinson Cancer Research Center/Prostate Cancer Research Institute/
Knight Cancer Institute-NIH/NCI/ PNW Prostate Cancer SPORE Developmental Research Program (DRP), Pilot Project Award
CMV-vectored Prostate Cancer Vaccine
We have generated a novel vaccine platform using cytomegalovirus as a vector that induces astonishing levels and breadth of effector memory T cell responses that we will use to attempt to break tolerance to self antigens associated with prostate cancer, in order to generate a curative prostate cancer immunotherapy. Role: Pl
NNN Picker (P!) 09/15/2011 - 06/30/2015 eee erate Collaboration for AIDS Vaccine Discovery (CAVD) evelopment of an Attenuated CMV Vector for an HIV/AIDS Vaccine The ultimate aim of this project is to develop a safe and effective HIV/AIDS vaccine for use in high burden countries. Role: Assistant Scientist
1 R41 Al109927-01A1 Streblow/Bruening (PI) 04/01/2014 — 03/31/2015
NIH/NIAID Advanced Technology STTR
CMV Vectored Herpes Simplex Vaccine
TomegaVax (PI Bruening) will generate wild type and spread-deficient murine CMV vaccine vectors that express fragments of HSV-2 ICPO and ICP4. The Streblow Lab will test the immunogenicity and protective efficacy of CMV vaccine vectors directed against HSV-2 in mice. Role: Co-PI
iedicien Friih/Streblow ~ 07/01/2014 — 06/30/2015
1e goal of this project is to use vectors to break tolerance to the prostate cancer associated protein PAP and by doing so elicit protective immune responses to the development of prostate cancer and metastatic disease. Role: Co-PI
5 RO1 Al089591-08 Diamond (PI) 09/01/2014 — 05/31/2015 NIH/NIAID
Antibody-Based Therapy of Chikungunya Virus
The major goal of this project is to generate an antibody therapy to control Chikungunya virus disease. Role: Subcontract P|
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: | @@@¥©O Ph.D.
RA COMMONS USER NAME (credential, e.g., agency login) I? POSITION TITLE: | ©@)@).®@ Drug Discovery
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) DEGREE Completion
(if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) | MM/YYYY
Medicinal Chemistry Medicinal Chemistry
A. Personal Statement
My training as a medicinal chemist and ears of experience in drug discovery and development provides the background to complete the proposed research. | have extensive experience in the development of novel therapeutics in the areas of oncology, neurobiology and infectious diseases. Currently, o 2omoe
Southern Research where we have several rams looking at new antibacterial
Moreover, | have extensive experience in working in large collaborations with other institutions, as well as with major pharmaceutical companies. Lastly, | serve as Co-Core Lead on of the Medicinal Chemistry and Development Core for our current Center of Excellence for Translational Research (CETR), Antiviral Drug Discovery and Development Center (AD3C).
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C. Contributions to Science
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lor MyBibli i
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D. Additional Information: Research Support and/or Scholastic Performance
ONGOING SUPPORT
Contact PD/PI: WHITLEY, RICHARD J.
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: OUGHANOG)
eRA COMMONS USER NAME (credential, e.g., agency login: es POSITION TITLE: Professor of Biochemistry and Biophysics
EDUCATION/TRAINING (Begin with baccélaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion INSTITUTION AND LOCATION (if Date BIELD ORSTUDY applicable; MM/YYYY BS Biology PhD Biochemistry/Virology Postdoctoral Retrovirology
A. Personal Statement
| began work on retroviruses as a postdoctoral fellow exploring questions related to viral replication and oncogenesis. As an assistant professor | moved into the HIV-1 field which has remained my main research focus. My initial studies on retroviruses focused on viral replication. This work helped define the structure of viral DNA and explored the genomic organization of a transduced oncogene which led to a model of oncogene transduction. My early work in HIV-1 focused on the identification and genetic characterization of the viral protease, followed by selection of resistance as protease inhibitors became available, and then the ordering of the proteolytic pathway. These continue to be active lines of research as a collaboration with
to develop improved protease inhibitors, and in our work to find maturation inhibitors that block processing at the MA/CA site, which may be the most sensitive site to inhibit replication. | carried an early interest in entry phenotype from avian retroviruses into HIV-1 where we initially studied the evolution of X4 viruses and have added the study of the evolution of macrophage-tropic viruses. Work with the HIV-1 env gene has provided a platform to explore questions of viral compartmentalization in the genital tract and the CNS. We have had to redefine the major form of HIV-1 as RS T cell-tropic as we have found macrophage-tropic viruses to be rare and largely confined to the CNS. The increasing power of sequencing technologies has been an important tool as we continue to explore HIV-1 biology and specifically in this application, as we are determining the mechanism of action for several lead candidates being evaluated as therapeutics to treat highly pathogenic
human coronaviruses. Training of the next generation of scientists has been intimately linked to my research wn ha en) en
B. Positions and Honors
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MyBibliograph
D. Additional Information: Research Support and/or Scholastic Performance
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OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: OAA.0O
eRA COMMONS USER NAME (credential, e.g., agency login): Oo
POSITION TITLE: Senior Project Manager
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
DEGREE Completion
(it applicable) Date FIELD OF STUDY INSTITUTION AND LOCATION MMWIYYYY OBA.0O &) G) A). &) ©) B.Sc. Biology Fn.0. Medical Microbiology Post-Doctoral pa eras Viral Oncology Senior Post-Doctoral Pulmonary Inflammation Fellow and Viral Exacerbation
A. Personal Statement mame
| am a bacteriologist/virologist/immunologist and molecular biologist with years of experience in researching medically-relevant pathogens at both pre-clinical and clinical levels. Currently, | serve as Senior Project Manager responsible for overseeing the influenza virology program, both in vitro and in vivo, at Southern Research. In addition, | lead the support effort for non-clinical and clinical sample testing by designing and executing validations or qualifications and managing sample analysis in partnership with both commercial and government clients. Prior to joining Southern Research in| ©@)@).®©), | was a Principal Investigator and Study Director for °“*years at a BSL3+/ABSL3+ contract research organization where | successfully conducted a GLP- compliant animal model qualification for an aerosolized Tier-1 Select Agent in nonhuman primates. In addition, | supervised and performed a broad range of procedures using novel and standard techniques and methods, including refining a number of animal models using both viral and bacterial species. Viral animal models were primarily mouse and ferret influenza models using seasonal, pandemic and highly pathogenic avian influenza strains. Influenza studies included testing new vaccine platforms for efficacy and conducting pathotyping studies to determine the safety of potential vaccine strains for newly emerged and pandemic influenza strains along with novel antivirals.
Note: Due to the contract nature of the work performed, most of my relevant works are not publishable.
They are considered proprietary information, are not publicly available, and may not be listed a “
) ) (6)
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C. Contributions to Science
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D. Research Support
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OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: [GYAN
eRA COMMONS USER NAME (credential, e.g., agency coin: eS
POSITION TITLE: Research Associate
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION BED OESUbY
Biology
Clinical Medicine Virology
A. Personal Statement
After my MD training, | worked at the research clinician. | was the domestic investi
| started to use Primer ID approach combined with next generation sequencing to study intra-host viral diversity, drug resistance mutations, viral co-receptor tropism. | adapted Primer ID approach
with Illumina MiSeq platform and resolved several issues with using Primer ID approach in viral genetic studies. | also developed bioinformatics tools written in RUBY to analyze Primer ID sequencing data. My research results of Primer ID encing were presented at several international conferences includin:
iced with next generation sequencing and the Primer ID approach: which is the key technique in the proposed study. My computational skills allow me to develop tools for downstream analysis.
B. Positions and Honors
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C. Contributions to Science
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Campiete List of Published Work in Mysioloar=ery
D. Additional Information: Research Support and/or Scholastic Performance
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Contact PD/PI: WHITLEY, RICHARD J. OMB Number: 4040-0010 Expiration Date: 10/91/2019
Project/Performance Site Location(s)
Project/Performance Site Primary Location O Lam submitting an application as an individual, and not on behalf of a company, state, local or tribal government, academia, or other type of
organization.
Organization Name: UNIVERSITY OF ALABAMA AT BIRMINGHAM Duns Number: 0636907050000
Streett*: UNIVERSITY OF ALABAMA AT BIRMINGHAM Street2: 1720 2nd Ave South, AB1170
City*: BIRMINGHAM
County:
State": AL: Alabama
Province:
Country*: USA: UNITED STATES
Zip / Postal Code*: 352940111
Project/Performance Site Congressional District": AL-007
Additional Location(s) File Name:
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Tracking Number: GRANT12598083 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
(OMB Number: 4040-0001 Expiration Date: 10/31/2019
RESEARCH & RELATED Other Project Information
1. Are Human Subjects Involved?" © Yes @ No 1.a. If YES to Human Subjects Is the Project Exempt from Federal regulations? O Yes O No If YES, check appropriate exemption number: at 8 28 o4 38 6 ~9 <8 If NO, is the IRB review Pending? O Yes O No IRB Approval Date: Human Subject Assurance Number 2. Are Vertebrate Animals Used?* 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? @ Yes O No IACUC Approval Date: Animal Welfare Assurance Number none
Yes O No
3. Is proprietary/privileged information included in the application?* @ Yes O No
4.a. Does this project have an actual or potential impact - positive or negative - on the environment?* © Yes @ No 4.b. If yes, please explain:
4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an © Yes O No environmental assessment (EA) or environmental impact statement (EIS) been performed?
4.d. Ifyes, please explain:
5. Is the research performance site designated, or eligible to be designated, as a historic place?* O Yes @ No
5.a. Ifyes, please explain:
6. Does this project involve activities outside the United States or partnership with international O Yes @ No collaborators?*
6.a. If yes, identify countries:
6.b. Optional Explanation:
Filename 7. Project Summary/Abstract* Summary_Overall_Final.pdf 8. Project Narrative’ Narrative_Overall_Final.pdf
9. Bibliography & References Cited Bibliography_Overall.pdf
10.Facilities & Other Resources Overall_Facilities.pdf
11.Equipment
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Tracking Number: GRANT 12598083 Funding Opportunity Number: RFA-Al-17-042. Received Date: 2018-03-29T 16:30:43.000-04:00
Contact PD/PI: WHITLEY, RICHARD J.
OVERALL SUMMARY
In response to RFA-Al-17-042, Centers of Excellence in Translational Research, we propose to develop small molecule therapeutics for the treatment of emerging viral infections under the umbrella of the Antiviral Drug Discovery and Development Center. We are a team of scientists experienced in virology, viral immunology, pathogenesis, medicinal chemistry, and translation to human disease. We have established four Projects — each of which addresses infections identified as high priority by the National Institute of Allergy and Infectious Diseases (NIAID). Members of several genera of RNA viruses will be studied as they are major causes of human disease, bioterrorist threats, or emerging infectious diseases. Pharmacological control of these viruses remains limited. Our Projects will focus on (1) coronaviruses that cause SARS and MERS, (2) alphaviruses including Venezuelan equine encephalitis virus and chikungunya, 3) flaviviruses including dengue, West Nile virus, and Zika and 4) influenza A virus. We will utilize lead molecules identified in recent years by AD3C to perform therapeutic proof of principle studies in animal models within the first two years of the grant. Importantly, we will additionally evaluate a limited number of novel compounds provided by our collaborators, the Emory Institute for Drug Discovery (EIDD) and Gilead Sciences in order to have back-up platforms to address the potential development of resistance. Expertise exists in the AD3C for IND enabling studies, IND preparation and filing as well as Phase | studies, should suitable candidates be identified. The projects are supported by three Cores: the Administrative Core (Core A), the Assay Core (Core B), and the Medicinal Chemistry and Lead Development Core (Core C). The organization and interaction between all Projects and Cores will be monitored by the Administrative Core. An Executive Committee (EC) will consist of all Project and Core Leads to review data on monthly conference calls, in order to provide further direction and foster project interactions. An external Scientific Advisory Committee (SAC) will be established to provide evaluation of the project progress and facilitate “Go/No-Go’” decisions on a regular basis. Since its inception, AD3C has already contributed significant data to an IND filed for MERS and two patent applications for compounds with activity against chikungunya, illustrating the success of our collaborative model.
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Project Summary/Abstract
Contact PD/PI: WHITLEY, RICHARD J.
OVERALL NARRATIVE
The purpose of the project is to develop therapies for emerging infections such as coronaviruses, dengue and chickungunya, which pose risks for traveling US citizens or could be imported into the country by others. We also strive to discover new drugs which could be used to treat infections for which we have limited or no treatments, such as influenza.
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Project Narrative
Contact PD/PI: WHITLEY, RICHARD J.
FACILITIES AND RESOURCES
The proposed CETR named the Antiviral Drug Discovery and Development Center (AD3C) is a collaboration between multiple institutions, including:
It wil
The University of Alabama at Birmingham (UAB)
Southern Research (SR)
Emory University, in particular the Emory Institute for Drug Development (EIDD) Vanderbilt University Medical Center (Vanderbilt)
The University of North Carolina at Chapel Hill (UNC-CH)
Oregon Health and Science University (OHSU)
The University of Colorado at Denver (UC-D)
The University of Texas Medical Branch at Galveston (UTMB)
Washington University (Wash U)
| cover 4 Research Projects with the support of 3 Cores; all Projects and 1 Core have multiple research sites:
Core A: Administrative Core o UAB Core B: Assay Core o SR Core C: Medicinal Chemistry and Lead Development Core o SR o EIDD Project 1: Coronavirus o Vanderbilt o UNC-CH Project 2: Alphavirus o OHSU o UNC-CH o UC-D Project 3: Flavivirus o UTMB o OHSU o Wash U Project 4: Influenza o UAB o SR
The facilities and resources for each institution site are described under the respective Project or Core components. The Administrative Core includes a write up that lists the various BSL3 facilities to be used in the proposed research.
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Facilities & Other Resources
Contact PD/PI: WHITLEY, RICHARD J. OMB Number: 4040-0001 Expiration Dato: 10/31/2019
RESEARCH & RELATED Senior/Key Person Profile (Expanded)
PROFILE - Project Director/Principal Investigator
Prefix: First Name*: RICHARD Middle Name J. Last Name*: WHITLEY Suffix: Position/Title*: Distinguished Professor
Organization Name*: University of Alabama at Birmingham
Department:
Division:
Street1* 1600 7th Avenue South
Street2: OOAOO
City*: Birmingham
County:
State*: AL: Alabama
Province:
Country": USA: UNITED STATES
Zip / Postal Code*: 352330000
Phone Number*: 205-934-5316 Fax Number: 205-934-8559
E-Mail*: rwhitley@peds.uab.edu
Credenti Project Role*: PD/PI Other Project Role Category: Degree Type: MD,AB Degree Year: 1971
File Name: RJW_Biosketch_current_AD3C. pdf