2 R42 AI138630-03 1 ZRG1 BCMB-G (10)

HARTY, R

PROGRAM CONTACT:

Application Number: 2 R42 AI138630-03

Principal Investigator Formerly: 3R41AI138630-02 

HARTY, RONALD N

Applicant Organization: FOX CHASE CHEMICAL DIVERSITY CENTER, INC

Review Group: ZRG1 BCMB-G (10)

Center for Scientific Review Special Emphasis Panel

Small Business Applications: Drug Discovery and Development

Meeting Date: 11/16/2020 RFA/PA: PA20-265

Council: JAN 2021 PCC: M55A B 

Requested Start: 04/01/2021

Project Title: Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses

SRG Action: Impact Score:

Next Steps: Visit https://grants.nih.gov/grants/next_steps.htm

Human Subjects: 30-Human subjects involved - Certified, no SRG concerns 

Animal Subjects: 30-Vertebrate animals involved - no SRG concerns noted

Gender: 1A-Both genders, scientifically acceptable

Minority: 1A-Minorities and non-minorities, scientifically acceptable 

Age: 7A-Only Adults, scientifically acceptable

Project Direct Costs Estimated

Year Requested Total Cost 

3 

4 

5 

TOTAL

ADMINISTRATIVE BUDGET NOTE: The budget shown is the requested budget and has not been adjusted 

to reflect any recommendations made by reviewers. If an award is planned, the costs will be calculated by 

Institute grants management staff based on the recommendations outlined below in the COMMITTEE 

BUDGET RECOMMENDATIONS section.

. 

SUMMARY STATEMENT

( Privileged Communication ) Release Date: 11/22/2020

Revised Date:

Text from the application is copyrighted. The awardee provided express permission for NIAID to post the 

grant application and summary statement for educational purposes. The awardee allows you to use the material 

(e.g., data, writing, graphics) they shared in the applications for nonprofit educational purposes only, provided 

the material remains unchanged and the principal investigators, awardee organizations, and NIH NIAID are 

credited. 

Freedom of Information Act (FOIA). NIAID is strongly committed to protecting the integrity and confidentiality 

of the peer review process. When NIH responds to FOIA requests for grant applications and summary 

statements, the material will be subject to FOIA exemptions and include substantial redactions. NIH must 

protect all confidential commercial or financial information, reviewer comments and deliberations, and personal 

privacy information. 

Contact Information. Email NIAID's Office of Knowledge and Educational Resources at deaweb@niaid.nih.gov
 

 

 

 

 

 

2 R42 AI138630-03 2 ZRG1 BCMB-G (10) 

HARTY, R 

2R42AI138630-03 HARTY, RONALD 

RESUME AND SUMMARY OF DISCUSSION: A very strong and experienced in drug discovery group 

from the Fox Chase Chemical Diversity Center proposes to continue the development of small 

molecules for the treatment of hemorrhagic fever viruses. The significance of the proposed work is 

exceptionally high as effective therapies for emerging human RNA viruses are urgently needed. The 

Phase I portion of the project was very successful and yielded a lead series with promising properties, 

including in vivo proof-of-concept. There is a solid foundation for further optimization of drug-like 

properties and demonstration of in vivo efficacy. The overall approach is well-conceived, logically 

presented and sufficiently detailed; supplemental information shows that the lead molecule also blocks 

release of live infectious SARS-CoV-2 from infected human lung cells, which is consistent with the 

mechanism of action. Few minor weaknesses associated with the unclear ‘new’ scaffolds do not detract 

from the very high enthusiasm the panel expressed for this comprehensive and likely impactful 

proposal. 

DESCRIPTION (provided by applicant): The ultimate goal of this Phase II application is to develop 

novel small molecule, broad-spectrum therapeutics against viral infections caused by filoviruses, 

arenaviruses, and other viruses that depend on the PPxY L-domain motif for egress and spread of 

infection. Some of these viruses, including Ebola (EBOV), Marburg (MARV), and Lassa fever (LAFV) 

viruses, are highly pathogenic and classified as Category A bioterror pathogens. We and others have 

determined that efficient budding of these emerging human pathogens depends on the subversion of 

host proteins, such as neural precursor cell expressed developmentally down-regulated protein 4 

(Nedd4), by PPxY L-domains in the matrix proteins of these RNA viruses. The identification and 

development of small molecule inhibitors that interfere with these virus-host interactions should 

effectively block virus egress, disease progression, and transmission. In these efforts we have 

discovered several chemical series of small molecule inhibitors of the host Nedd4/virus PPxY complex 

important for viral egress which led to one analog possessing proof of concept in vivo activity in a 

Marburg virus challenged mouse model. As FDA approved therapeutic agents for the treatment of 

these most of these viral infections are not available, our identification of virus-host inhibitors that may 

prevent virus spread will fill a significant unmet need. Moreover, these inhibitors will be broad-spectrum, 

and therefore will likely be effective against newly emerging viruses as well as viral variants. As 

described below, we will use a rigorous multifaceted approach to identify, develop, and validate PPxY 

budding inhibitors identified in Phase I as potent, broad-spectrum antivirals. The goal of this Phase II 

STTR grant application is to optimize our lead inhibitors of VP40 PPxY-Nedd4 interactions to generate 

full- fledged predevelopment drug candidates ready for IND directed studies. This will be accomplished 

by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase 

Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience in the experimental aspects 

of antiviral therapy of the Harty Lab at the University of Pennsylvania. We will realize this goal by 

optimizing our existing series of inhibitors, exemplified by in vivo active FC-10696, for improved potency 

and oral drug properties (Aim 1), evaluating new compounds based on two potent series for their ability 

to specifically inhibit PPxY-Nedd4 interactions and subsequent VLP and surrogate virus egress (Aim 2), 

identifying compounds having suitable drug properties and selectivity using in vitro and in vivo ADMET 

evaluation (Aim 3), and evaluating compounds for their antiviral efficacy against authentic BSL-4 

viruses in vitro and in vivo (Aim 4). 

PUBLIC HEALTH RELEVANCE: There is an urgent need to develop antiviral therapy against 

emerging human RNA viruses that represent potential agents of bioterrorism (Ebola, Marburg, and 

Lassa fever). We have discovered small molecule compounds that disrupt budding and spread of live 

viruses; a process that is critical for virus dissemination and disease progression. Here, the Harty group 

at the University of Pennsylvania, experts in the antiviral technology of this proposal, have partnered 
 

 

 

2 R42 AI138630-03 3 ZRG1 BCMB-G (10) 

HARTY, R 

with the small business Fox Chase Chemical Diversity Center, Inc. to further develop these broad 

spectrum antiviral budding inhibitors by using medicinal chemistry, live virus budding assays, and live 

cell imaging techniques. 

CRITIQUE 1 

Significance: 

Investigator(s): 

Approach: 

Innovation: 

Environment: 

Overall Impact: The overall impact of this Phase II STTR proposal to develop effective therapies for 

RNA viruses caused by Marburg and Ebola, is very high. These are also rare diseases, and the 

investigators can benefit from that designation along with being eligible for the US neglected disease 

voucher program. The scientific rigor from the data obtained from the Phase I study is strong with the 

identification of two lead series of compounds and an advanced lead compound with very good 

potency. The strategy to block the viral-host interactions between the matrix protein PPxY and select 

host proteins for efficient virus egress (cellular budding) and spreading infection appears innovative. 

The strong premise of the project plan with the potential to identify a preclinical candidate that could 

lead to acute toxicity study phase of the pre-IND. The details of a screening cascade, target product 

profile and go no-go decisions, and a robust commercialization plan with options, provide confidence 

that this well rounded team can execute the current objectives and has the high potential to nominate a 

clinical candidate from this project. The resources lined up and the facilities that will be used to conduct 

the proposed studies and the strength of a world class team assembled around this project has made 

this a highly impactful proposal. 

1. Significance: 

Strengths 

• There is an unmet need to develop effective therapeutics to protect immunologically naïve 

individuals form the RNA virus infections as the Marburg and Ebola viruses cause hemorrhagic 

diseases, which is a rare disease. 

• Currently available vaccines are not a complete defense since they must be given preexposure. 

• The therapeutic development program for these diseases is eligible for the US neglected 

disease voucher program. 

Weaknesses 

• None noted. 

2. Investigator(s): 

Strengths 

• Excellent team of interdisciplinary scientists spanning computation chemistry, medicinal 

chemistry, virology, with extensive experience in drug discovery and development in Pharma. 

• The team also has collaborated for the Phase I STTR grant and on other projects. 
 

 

 

 

2 R42 AI138630-03 4 ZRG1 BCMB-G (10) 

HARTY, R 

• Business Development expertise is included, which is essential for executing the 

commercialization strategy. 

Weaknesses 

• None noted. 

3. Innovation: 

Strengths 

• Developing therapeutics to block viral-host interactions. 

• Novel series of Nedd4:PPxY inhibitors targeting the virus-host interactions, of a conserved 

host:virus complex to develop broad spectrum antivirals to treat Marburg and other emerging 

RNA viruses. 

Weaknesses 

• None noted. 

4. Approach: 

Strengths 

• Advanced lead compound has nanomolar potency with no potential Cy P450 3A4 activity and 

good metabolic stability. 

• The proposed optimization of advanced lead FC-10696 to identify 2-3 compounds with 

improved aqueous solubility while continuing to improve their potency, TI, ADME, PK and safety 

properties specific criteria (screening cascade given), testing for potency and in vitro/in vivo 

evaluation of promising inhibitors against other RNA viruses is executable. 

• The proposed work has the potential to develop improved analogs that inhibit RNA viral egress, 

due to inhibition of viral matrix protein PPxY interaction with cellular Nedd4. 

Weaknesses 

• As the Phase I grant is currently under a no-cost extension, it is not clear if the Phase II grant 

will be contingent on completing the proposed Phase I objectives. 

5. Environment: 

Strengths 

• The facilities at the Texas Biomedical Research Institute, and the resources available at the 

CRO are adequate for executing the project. 

Weaknesses 

• None noted. 

Phase II (Type 2 R42 and Type 2 R44 applications) 

Acceptable 

• The progress made from the Phase I study shows robust data with POC in vivo reduction of 

Marburg virus challenged mouse models. 
 

 

2 R42 AI138630-03 5 ZRG1 BCMB-G (10) 

HARTY, R 

• A clear product development plan with desired TPP and a robust commercialization plan 

options, with strong IP protection on composition of matter (issued). 

Protections for Human Subjects: 

Acceptable Risks and Adequate Protections 

Vertebrate Animals: 

YES, all criteria addressed 

Biohazards: 

Acceptable 

Select Agents: 

Acceptable 

Resource Sharing Plans: 

Acceptable 

Authentication of Key Biological and/or Chemical Resources: 

Acceptable 

Budget and Period of Support: 

Recommend as Requested 

CRITIQUE 2 

Significance: 

Investigator(s): 

Innovation: 

Approach: 

Environment: 

Overall Impact: This Phase II STTR application aims to develop novel small molecule, broad-spectrum 

antivirals against infections caused by filoviruses, arenaviruses, and other viruses that depend on the 

PPxY L-domain motif for virus egress and spread of infection [Marburg (MARV), Ebola (EBOV), and 

Lassa fever (LAFV)]. There are no commercially available small molecule therapeutics for these viral 

infections. The proposed anti-virals will fill a significant unmet need. The team has discovered several 

chemical series that block the host Nedd4/virus PPxY complex (critical regulator of viral transmission) 

and have identified an analog capable of blocking in vivo activity in a Marburg virus challenged mouse 

model as proof of concept. In the current proposal they will use their current lead inhibitor series, (e.g., 

FC-10696) to generate novel candidates for IND-enablement studies. To accomplish this goal, 
 

 

 

2 R42 AI138630-03 6 ZRG1 BCMB-G (10) 

HARTY, R 

scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC; pharmaceutical and medicinal 

chemistry), the Harty Lab at the University of Pennsylvania (experimental aspects of antiviral therapy), 

and the lab of Olena Shtanko at Texas Biomedical Research Institute (evaluating compounds against 

live viruses in vitro and in vivo under BSL-4 conditions) have combined their considerable experience 

and expertise. The team of researchers has extensive expertise in relevant areas and are a major 

strength. Preliminary data provided in the proposal indicate that the approach is promising and newly 

designed leads exhibit antiviral activity. The overall approach is well conceived, is based on solid 

literature precedent, and addresses the major aspects required of a drug discovery program. In 

addition, supplements (Additional Materials) recently submitted by the PI suggest the compounds under 

development may have the potential to serve as broad-spectrum antivirals against emerging pathogens 

(e.g., SARS-Co-V-2). There is considerable enthusiasm for the project with only minor concerns. 

1. Significance: 

Strengths 

• The project addresses an important, current need for effective anti-viral therapy. 

• The novel agents presented potently interrupt the host Nedd4: viral PPxY interaction to inhibit 

virus budding and spread. 

• If the project is successful it could lead to a novel, much needed antiviral treatment. 

• The scientific premise is well supported by literature reports. 

• The team has experience with antivirals and a history in the drug discovery area. 

Weaknesses 

• None noted. 

2. Investigator(s): 

Strengths 

• The PI and the team of scientists are highly qualified to carry out the proposed work. 

• The team has a successful track record of productivity in this area of research. 

Weaknesses 

• None noted. 

3. Innovation: 

Strengths 

• Interrupting the host Nedd4: viral PPxY interaction to inhibit virus budding and spread is 

innovative. 

• The small molecule inhibitors being proposed in the current proposal are novel. 

• The potential for the newly discovered, novel inhibitors to have broad antiviral indications is 

high. 

Weaknesses 

• None noted. 
 

 

 

 

2 R42 AI138630-03 7 ZRG1 BCMB-G (10) 

HARTY, R 

4. Approach: 

Strengths 

• Efforts to improve PK/PD profiles of leads (metabolic stability, solubility, etc.) via molecular 

modification in the medicinal chemistry plan is rational and clearly described. 

• The group has experience with the assay used to test compounds for their ability to specifically 

inhibit the PPxY-Nedd4 interaction and subsequent virus egress. 

• A well designed, three-pronged approach is utilized under BSL-2 conditions to identify the best 

compounds (Aim 2) to be advanced to the more challenging and hazardous studies in the BSL4 laboratory (Aim 4). 

• In vitro and in vivo ADMET evaluation of lead compounds will be performed to ensure suitable 

drug properties and selectivity (FCCDC). 

• In vitro and in vivo analyses of lead inhibitors against authentic hemorrhagic fever viruses is 

performed in a BSL4 laboratory at Texas Biomedical Research Institute (TBRI; Dr. Olena 

Shtanko). 

• A high level of scientific rigor is evident throughout the proposal. 

Weaknesses 

• The rationale for the “new” scaffolds proposed in Aim 1 (increase basicity) is unclear and may 

present additional challenges following incorporation into inhibitors. 

5. Environment: 

Strengths 

• The resources available at each of the sites are more than adequate to carry out the proposed 

work. 

Weaknesses 

• None noted. 

Phase II (Type 2 R42 and Type 2 R44 applications) 

Acceptable 

• The team successfully completed a phase I grant that supplied proof of concept for their antiviral 

leads. The current proposal builds on that work to provide drug-like anti-viral agents for INDenabling studies. 

Protections for Human Subjects: 

Acceptable Risks and Adequate Protections 

• The research involves human subjects as a source of blood obtained by venipuncture to isolate 

peripheral blood mononuclear cells. Studies in primary human macrophages (targets of MARV, 

EBOV, LASV) are important to understand whether antiviral treatment affects virus replication 

and spread in clinically relevant cells. Subjects are limited to normal healthy adult (18-50 years 

old) volunteers without symptoms. Both genders are studied and there is no discrimination of 

race or ethnicity. Participant recruitment will also be monitored. Risks will be explained to the 

subject by the principal investigator or an appropriate physician representative. 
 

2 R42 AI138630-03 8 ZRG1 BCMB-G (10) 

HARTY, R 

Inclusion Plans: 

• Sex/Gender: Distribution justified scientifically 

• Race/Ethnicity: Distribution justified scientifically 

• Inclusion/Exclusion Based on Age: Distribution justified scientifically 

• Subjects are limited to normal healthy adult (18-50 years old) volunteers without symptoms. 

Both genders are studied and there is no discrimination of race or ethnicity. Participant 

recruitment is monitored. Risks will be explained to the subject by the principal investigator or 

an appropriate physician representative. 

Vertebrate Animals: 

YES, all criteria addressed 

• Justifications for animal use, protection of animals during studies and method of euthanasia are 

described (where appropriate). 

Biohazards: 

Acceptable 

Select Agents: 

Acceptable 

Resource Sharing Plans: 

Acceptable 

Authentication of Key Biological and/or Chemical Resources: 

Acceptable 

Budget and Period of Support: 

Recommend as Requested 

Recommended budget modifications or possible overlap identified: 

• The budget goes beyond the statutory guidelines for Phase II STTRs. The budget waiver is 

elected. 

CRITIQUE 3 

Investigator(s): 

Significance: 

Innovation: 

Approach: 
 

2 R42 AI138630-03 9 ZRG1 BCMB-G (10) 

HARTY, R 

Environment: 

Overall Impact: This is a strong proposal for the development of small molecules for treatment of 

hemorrhagic fever viruses. Their Phase I work yielded a lead series with promising properties, including 

in vivo proof-of-concept. Phase II is focused on further optimization of drug-like properties and 

demonstration of in vivo efficacy. The supplemental information shows that the lead molecule also 

blocks release of live infectious SARS-CoV-2 from infected human lung cells, which is consistent with 

the MOA. Overall, a strong proposal with clear goals for optimization and an effective screening tier that 

will give confidence in the develop-ability of an optimized lead. 

1. Significance: 

Strengths 

• High unmet medical need for treatment of highly pathogenic viruses such as Ebola, Marburg, 

and Lassa viruses; potential for application to SARS-CoV-2 (supplementary material). 

• Application to viral treatment in both community settings and in response to bioterrorist use of 

the hemorrhagic viruses. 

Weaknesses 

• None noted. 

2. Investigator(s): 

Strengths 

• Strong expertise in all aspects of the project. Harty is an expert in the area of RNA virus-host 

interactions and virus egress/transmission. Investigators have impressive track records of 

success in their disciplines. 

Weaknesses 

• None noted. 

3. Innovation: 

Strengths 

• Novel mechanism of action via blocking the host Nedd4/virus PPxY complex, a critical regulator 

of viral transmission. 

• Lead series identified; one member has demonstrated in vivo proof-of-concept in a Marburg 

virus mouse model. 

Weaknesses 

• None noted. 

4. Approach: 

Strengths 

• Plan for optimization is clearly laid out and logical in progression; timelines are reasonable. 
 

 

2 R42 AI138630-03 10 ZRG1 BCMB-G (10) 

HARTY, R 

• Challenges in the lead structure are acknowledged (e.g., high logD, likely low aqueous 

solubility) and plans to address are specifically mentioned. Criteria for success are clearly 

delineated. 

• Ability to screen in an in vivo viral infection model is a significant strength. 

• Early consideration of a prodrug strategy is reasonable given that the SAR may not permit 

modifications that give increased solubility. 

Weaknesses 

• None noted. 

5. Environment: 

Strengths 

• All appropriate facilities are available. 

• Access to ABS-L4 labs is critical to evaluation of the lead molecules. 

Weaknesses 

• None noted. 

Phase II (Type 2 R42 and Type 2 R44 applications) 

Acceptable 

Protections for Human Subjects: 

Acceptable Risks and Adequate Protections 

• The need for human blood samples is clearly described (human peripheral blood mononuclear 

cells are needed to study antiviral efficacy), as are protection of privacy and protection against 

risks. 

Inclusion Plans: 

• Sex/Gender: Distribution justified scientifically 

• Race/Ethnicity: Distribution justified scientifically 

• Inclusion/Exclusion Based on Age: Distribution justified scientifically 

• Subjects are limited to normal healthy adult (18-50 years old) volunteers without symptoms. 

Both genders are studied and there is no discrimination of race or ethnicity. 

Vertebrate Animals: 

YES, all criteria addressed 

• Acceptable; mice will be used for DMPK and in vivo efficacy studies; animal care and use is 

appropriately documented, as is the need for use of animals. 

Biohazards: 

Acceptable 
 

2 R42 AI138630-03 11 ZRG1 BCMB-G (10) 

HARTY, R 

Select Agents: 

Acceptable 

Resource Sharing Plans: 

Acceptable 

Authentication of Key Biological and/or Chemical Resources: 

Acceptable 

Budget and Period of Support: 

Recommend as Requested 

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO 

SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' 

WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: 

PROTECTION OF HUMAN SUBJECTS: ACCEPTABLE 

INCLUSION OF WOMEN PLAN: ACCEPTABLE 

INCLUSION OF MINORITIES PLAN: ACCEPTABLE 

INCLUSION ACROSS THE LIFESPAN: ACCEPTABLE 

VERTEBRATE ANIMALS: ACCEPTABLE 

COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. 

Footnotes for 2 R42 AI138630-03; PI Name: HARTY, RONALD N 

NIH has modified its policy regarding the receipt of resubmissions (amended applications).See 

Guide Notice NOT-OD-18-197 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-

197.html. The impact/priority score is calculated after discussion of an application by 

averaging the overall scores (1-9) given by all voting reviewers on the committee and 

multiplying by 10. The criterion scores are submitted prior to the meeting by the individual 

reviewers assigned to an application, and are not discussed specifically at the review meeting 

or calculated into the overall impact score. Some applications also receive a percentile 

ranking. For details on the review process, see 

http://grants.nih.gov/grants/peer_review_process.htm#scoring.