# Multimeric HIV-1 Integrase Inhibitors

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $502,002

## Abstract

Abstract
The overarching goals of the present proposal are to develop first-in-class multimeric HIV-1 integrase (IN)
inhibitors (MINIs) for their future clinical development and to exploit these compounds as powerful investigational
tools for HIV-1 molecular biology to uncover critical molecular interactions during maturation. Because of their
unique mode of action, MINIs are expected to potently inhibit all drug resistant viral phenotypes in the clinic,
which continually evolve in response to currently used ARTs. By rationally modifying archetypal, multifunctional
quinoline-based allosteric IN inhibitors (ALLINIs), we have developed highly potent pyridine-based MINIs, which
are highly selective for inducing hyper-multimerization of IN. Our SAR studies have been critical for
understanding the antiviral mode of action of these inhibitors and allowed us to clearly delineate the significance
of HIV-1 IN multimerization as a novel, attractive therapeutic target. We have shown this hyper-multimerization
of IN occurs in viral particles during maturation, which in turn impairs IN binding to the viral RNA genome and
results in eccentric, non-infectious virions with ribonucleoprotein complexes being displaced outside of the
protective capsid core. In addition, our rational design approach enabled us to develop a lead compound, MINI
KF116, with a markedly enhanced genetic barrier to resistance compared with its ALLINI counterparts. In
particular, KF116 is fully active against the HIV-1 variant with an A128T IN substitution, which confers resistance
to the majority of archetypal ALLINIs. Instead, triple (T124N/V165I/T174I) IN substitutions, which significantly
compromise viral replication even with a compensatory V165I mutation, are necessary to confer resistance to
KF116. Collectively, our findings argue that pyridine-based KF116 is as an excellent platform for the development
of second generation MINIs. Our future work will extend these studies and build on our exciting new preliminary
results, which show that MINIs/ALLINIs exhibit striking preference for full-length wild type IN tetramers.
Specifically, we found that inhibitor binding to the catalytic core domain (CCD) dimer is not sufficient for its activity
and that the CCD-inhibitor-C-terminal domain interactions between adjoining full-length IN tetramers are
necessary to induce hyper-multimerization of IN. Accordingly, we propose to dissect unique structural features
of IN tetramers as authentic targets for MINIs and ALLINIs (aim 1) and utilize this information to optimize second
generation inhibitors for their future clinical development (aim 2). The proposed studies are highly
complementary to and will synergize with very active ongoing efforts in the pharmaceutical industry to translate
the first-in-class MINIs/ALLINIs into the clinic with the ultimate goal of delivering safer next generation
therapeutics.

## Key facts

- **NIH application ID:** 9893809
- **Project number:** 5R01AI143649-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mamuka Kvaratskhelia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,002
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893809

## Citation

> US National Institutes of Health, RePORTER application 9893809, Multimeric HIV-1 Integrase Inhibitors (5R01AI143649-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893809. Licensed CC0.

---

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