# Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $538,140

## Abstract

PROJECT SUMMARY
 The HIV-1 capsid (CA) is a protein that plays a major role in multiple steps of the virus life cycle. During the
previous funding cycle we solved the elusive structure of the intact native full length hexameric HIV-1 CA
revealing previously unknown molecular details, especially at the 3-fold and 2-fold intra-hexamer interfaces that
affect core stability. We also solved >45 CA structures that include mutations that modulate core stability, thus
providing the first glimpses of the molecular basis of core stabilization that is critical in designing potential
therapeutics. Additional structures were in complex with host factor peptides, or a variety of novel inhibitors. In
addition, we synthesized and characterized >220 compounds that target the PF74-binding pocket. Among them
are compounds with much higher potency than PF74, and importantly, compounds with improved resistance
profile compared to GS-6207, a highly potent CA-targeting drug in clinical trials. In addition to strong CA hexamer
stabilizers, we introduced an innovative class of compounds, “destabilizers” of CA hexamers, raising the exciting
prospect of core destabilization that may lead to premature capsid uncoating and interferon upregulation.
 We will use a combination of chemical synthesis, virological, biophysical, and crystallography approaches to
synthesize a number of compounds that improve potency through new inter- and intra-protomer interactions;
overcome GS-6207 resistance mutations; modulate core stability and upregulate interferon response; enable
interactions with CA through innovative mechanisms, including covalent crosslinking. The compounds will be
characterized and the structure activity relationship studies will be guided by X-ray crystallography, biophysical
studies (time-lapse imaging, thermal shift, assembly kinetics assays) and virological characterization of
mechanism of action as well as drug resistance studies. The research will be conducted by the groups of Stefan
Sarafianos at Emory Univ (structure, biophysics, virology) and ZQ Wang (chemical synthesis, Univ of
Minnesota), Eric Freed at DRP-NCI (virology), and in collaboration with Greg Melikian (imaging).
 The proposed studies will advance our understanding of the structural basis of core stability, which controls a
large number of steps in the virus life cycle. They will also lead to the identification of innovative compound leads
with novel “CA-destabilizing” mechanisms of action, high potency, improved resistance profiles, CA-crosslinking
functionalities, and improved pharmacological properties.

## Key facts

- **NIH application ID:** 10437037
- **Project number:** 5R01AI120860-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Stefan G Sarafianos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $538,140
- **Award type:** 5
- **Project period:** 2016-03-16 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437037

## Citation

> US National Institutes of Health, RePORTER application 10437037, Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles (5R01AI120860-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10437037. Licensed CC0.

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