# Development of Lead Inhibitors of HIV Vif Binding to Antiretroviral A3G Through Medicinal Chemistry

> **NIH NIH R43** · OYAGEN, INC. · 2020 · $286,431

## Abstract

Project Summary
The HIV host restriction factor APOBEC3G (A3G) can inhibit HIV by inducing catastrophic
mutations in the viral genome. The HIV Vif protein protects HIV by binding to A3G and directing
it to the proteasomal degradation pathway. The significance of the proposed SBIR phase I
research is that Vif remains a new antiviral target whose clinical potential has yet to be fully
explored. Despite much academic research on Vif, only a limited effort has gone toward identifying
small molecule antagonists of Vif. OyaGen, Inc. is the only commercial entity currently pursuing
the identification of chemical scaffolds that specifically interact with Vif in meaningful ways for
drug development. An inherent limitation of prior anti-Vif drug discovery efforts has been the use
of primary drug screens in which ‘hits’ may be due to more than one mechanisms of action. We
designed a live cell quenched FRET (FqRET) reporter assay that enables selection of membrane-
permeable antagonists of protein-protein interactions between Vif and A3G using a Vif mutant
that retains wild type binding to A3G but no longer binds to Elongin C and no longer facilitates
A3G degradation. From a screen of a 110K small molecule library of drug-like compounds we
identified 165 prioritized his for further analysis. Although a few compounds were dose-dependent
antagonists of Vif binding of A3G, one compound, hereafter referred to as C5, was non-cytotoxic
and displayed dose-dependent: i) inhibition of Vif-dependent A3G degradation, ii) inhibition of
pseudotyped HIV replication and iii) promoted an increased incorporation of A3G in virions. Here
we propose an innovative drug discovery critical path to optimize a novel anti-HIV lead compound
from C5 in anticipation of phase II SBIR pharmacokinetic analysis, in vivo efficacy testing, and
IND-enabling studies. The Phase I SBIR Aims will focus on structure-activity relationship (SAR)
medicinal chemistry of the C5 scaffold for hit-to-lead optimization of anti-HIV compound whose
antiviral activity is mechanistically due to its function as a Vif antagonist that protects A3G from
Vif-dependent degradation.

## Key facts

- **NIH application ID:** 10079868
- **Project number:** 1R43AI155113-01
- **Recipient organization:** OYAGEN, INC.
- **Principal Investigator:** Jason Douglas Salter
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $286,431
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079868

## Citation

> US National Institutes of Health, RePORTER application 10079868, Development of Lead Inhibitors of HIV Vif Binding to Antiretroviral A3G Through Medicinal Chemistry (1R43AI155113-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10079868. Licensed CC0.

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