# Structural and Chemical Analysis of Highly Potent ALLINI Platform

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $464,005

## Abstract

Project Summary – Kim
HIV-1 integrase (IN) is one of the major antiviral targets, and multiple IN inhibitors have been developed as a
key component of current antiretroviral therapy (ART). However, considering viral resistance and toxicity
potentials of current INSTIs, compounds with new modes of action (MOA), improved safety profiles, high
genetic barrier, and long-acting formulation potentials still remain highly in demand. Allosteric IN inhibitors
(ALLINIs) are a new class of IN inhibitors that target the non-catalytic sites of HIV-1 IN. Initially, ALLINIs were
originally developed to block the binding of a host factor, LEDGF/p75, to the cleft formed between two IN
monomers. The binding of IN to LEDGF/p75, which is a transcription factor, facilitates the selection of viral
integration sites toward actively transcribed genes, which can facilitate LTR-mediated viral transcription post
integration. Also, it was later discovered that the binding of these ALLINI compounds targeting the LEDGF/p75
binding site of IN also inhibit HV-1 maturation by inducing aberrant IN multimerization that blocks the IN-viral
RNA interaction essential for the proper localization of viral genomes within viral capsid during viral maturation.
This new activity of IN during HIV-1 maturation further re-enforced the discovery efforts of ALLINI compounds
as a potential new class of antivirals (maturation inhibitors). However, after more than a decade of efforts, no
ALLINI compounds have progressed to clinical developments, due to their apparent toxicity or limited efficacy.
STP0404 is a highly potent pyrrolopyridine-based ALLINI with a sub-nanomolar IC50 efficacy, outstanding PK,
and safety profiles observed in both preclinical in vitro and animal investigations. This grant has been
supporting various intense MOA investigations of STP0404, which, together with extensive cellular and animal
PK and toxicology evaluations conducted by ST Pharm, STP0404 was recently moved to human trials. Indeed,
STP0404 became the first-in-human (FIH) ALLINI compound: the phase I trial of STP0404, which was
completed in 2022, demonstrated its outstanding safety and human PK profile for once-a-day oral formulations,
which further supports advanced clinical evaluations for its anti-viral efficacy in HIV-1 patients. In this renewal
application, we will characterize a new STP0404 derivative, EKC110, designed to have improved genetic
barrier and altered resistant mutation profile, and also investigate its cellular pharmacology/safety, and synergy
with other ART agents. We will also investigate novel antiviral activity and resistance MOAs of our
pyrrolopyridine ALLINIs by employing a series of biochemical, structural biology, virological, and computational
biology approaches. Finally, we will investigate the effect of STP0404 and EKC110 on HIV-1 integration site
selection and their HIV-1 reactivation suppression activity from latently infected CD4+ T cells. Overall, we aim
to deliver a new class of s...

## Key facts

- **NIH application ID:** 10838902
- **Project number:** 2R01AI141327-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Baek Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,005
- **Award type:** 2
- **Project period:** 2018-09-24 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838902

## Citation

> US National Institutes of Health, RePORTER application 10838902, Structural and Chemical Analysis of Highly Potent ALLINI Platform (2R01AI141327-06A1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10838902. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*