# New Inhibitors Targeting HIV-1 Integrase During Viral Maturation

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN MISSISSIPPI · 2021 · $355,517

## Abstract

Abstract
 HIV-1 integrase (IN) is validated clinical target and is essential for viral replication. During the early
steps of infection, tetrameric IN associates with two viral DNA ends and catalyzes their integration into the
host chromosome. A new class of allosteric IN inhibitors (ALLINIs) has been reported to inhibit enzyme
function by promoting aberrant IN multimerization. Interestingly, in infected cells these compounds
impaired both early and late stages of HIV-1 replication. In particular, the ALLINI-treated virions were
found to display profound viral core morphologies defects similar to those observed with several
replication-defective class II IN mutants. Collectively, these studies have suggested that in addition to
its known catalytic function in early stage, IN also plays an essential and non-catalytic role during the
late stage of HIV-1 replication. We were recently able to discover that IN binds to several viral RNA
(vRNA) elements and that ALLINIs strongly modulate these interactions in the virion. In addition, we
observed that IN can bring these bound vRNA elements together suggesting a possible role in vRNA
condensation. The present application will test the following hypothesis: IN-vRNA interactions and IN
oligomerization which are both critical for the correct formation of infectious virions can be targeted by
small molecule inhibitors. In aims 1, we will fully characterize the IN-vRNA complex and elucidate the
significance of the proper IN multimerization for vRNA binding and particle maturation. In aims 2, we
will design new IN inhibitors capable of modulating IN-vRNA binding and particle maturation.
Mechanistic and molecular details that will emerge from these studies will guide future drug targeting
initiatives of these critical non-catalytic IN functions in late stage of the viral replication.

## Key facts

- **NIH application ID:** 10218004
- **Project number:** 5R01AI140985-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN MISSISSIPPI
- **Principal Investigator:** Jacques J. Kessl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,517
- **Award type:** 5
- **Project period:** 2019-08-08 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218004

## Citation

> US National Institutes of Health, RePORTER application 10218004, New Inhibitors Targeting HIV-1 Integrase During Viral Maturation (5R01AI140985-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218004. Licensed CC0.

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