# Anti-HIV and anti-reactivation activities of pyrrolopyridine-based ALLINIs

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $45,620

## Abstract

Project Summary
The overarching obstacle in obtaining a functional cure for the 37.9 millions of people living with HIV globally is
eliminating the HIV-1 reservoirs. Viral integrase (IN) establishes lifelong infection in transcriptionally inactive but
replication competent cells by IN integrating proviral DNA into the host chromosome. The localization of
integration is directed by host factor LEDGF/p75 binding IN tethering to active transcriptional gene dense regions
of DNA. HIV-1 IN is one of the major antiviral targets, and multiple IN inhibitors (INSTs) have been developed
as a key component of current antiretroviral therapy (ART) but are subjected to viral resistance, cross-resistance
and toxicity. Rapid development of IN antivirals with high genetic barrier, new modes of action (MOA), with safe
DMPK profiles are in immediate need. Allosteric IN inhibitors (ALLINIs) are a new class of IN inhibitors targeting
non-catalytic sites of HIV-1 IN. STP0404 is a pyrrolopyridine-based ALLINI with outstanding efficacy, PK and
safety profiles observed in both preclinical in vitro and animal investigations. STP0404 became the first-in-human
(FIH) ALLINI compound demonstrating its outstanding safety and human PK profile for once-a-day oral
formulations, which further supports advanced clinical evaluations for its antiviral efficacy in HIV-1 patients. To
this effect, I propose to explore a new 2nd-generation ALLINI compound our laboratory designed for potentially
improved genetic barrier and possible utility as an HIV-1 cure agent. I have identified A128T IN mutant rendering
viral resistance to STP0404, and our X-ray structural study confirmed the longer side chain of A128T clashes
against 3-methyl group at the pyrrole moiety of STP0404, contributing to the reduced binding affinity to STP0404
and viral resistance to STP0404. To avoid contact between the A128T mutant and the methyl group of STP0404,
our group recently synthesized a new STP0404 derivative, EKC110, with missing the methyl group contacting
the A128T side chain. Here, I propose to test the hypothesis that EKC110 shows improved genetic barrier
with altered resistance mutation profiles, compared to the parental STP0404. Our preliminary data has
supported this hypothesis, additionally emerging evidence has reported ALLINIs blocking LEDGF/p75 binding
to IN, called LEDGINs, can drive the integration site specificity of HIV-1 toward non-actively transcribed regions
of the chromosomes, reducing HIV-1 reactivation from latently infected T cell reservoirs. In Aim 1, I will
investigate a new STP0404 derivative, EKC110 using molecular, virological and cell biological techniques for its
genetic barrier, viral resistance, antiviral MOA to determine the impact of structural modifications on HIV-1
antiviral activity. Aim 2, I will investigate the effect of STP0404 and EKC110 on HIV-1 integration site selection
and reactivation suppression from HIV-1 latently infected T cells using biochemical, molecular, and c...

## Key facts

- **NIH application ID:** 10762564
- **Project number:** 1F31AI179421-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** LINDSEY RAMIREZ
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $45,620
- **Award type:** 1
- **Project period:** 2023-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762564

## Citation

> US National Institutes of Health, RePORTER application 10762564, Anti-HIV and anti-reactivation activities of pyrrolopyridine-based ALLINIs (1F31AI179421-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10762564. Licensed CC0.

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