# Covalent capture of small molecule - gp41 complexes

> **NIH NIH R21** · TOURO UNIVERSITY OF CALIFORNIA · 2020 · $178,750

## Abstract

ABSTRACT
This is an exploratory proposal to develop new anti-HIV compounds that will inhibit entry of the virus into
human host cells by targeting gp41, the protein responsible for fusion of viral and host cell membranes. The
project utilizes synthetic organic chemistry, NMR structure determination, computational docking and energy
minimization, X-ray crystallography of protein – ligand complexes and biophysical and biological evaluation of
potency and mechanism. The specific focus of the proposal is development of molecules with chemical
reactive groups that can form covalent links with residues in the binding site. Recent research in this area has
revealed the propensity for covalent association to dramatically increase the potency of small molecule
inhibitors by extending the lifetime of the complexes formed with protein targets. The specific target on gp41 is
a highly conserved hydrophobic pocket that is exposed during the process of fusion and plays a key role in
stabilizing the post-fusion structure required for a successful fusion event. The hydrophobic pocket contains
lysine, glutamine and threonine residues that will be the target of the covalent inhibitors. Boron chemistry will
be used to generate reversible covalent bonds that stabilize the complexes but will avoid off-target effects and
consequently potential toxicity. Development of low molecular weight fusion inhibitors has been an elusive but
attractive goal, because of the potential to obtain orally available drugs that can prevent the initial infection of
cells and are likely to have a high barrier to resistance. Thus the work proposed represents an important new
direction towards developing nM small molecule inhibitors of fusion.

## Key facts

- **NIH application ID:** 9824573
- **Project number:** 5R21AI140904-02
- **Recipient organization:** TOURO UNIVERSITY OF CALIFORNIA
- **Principal Investigator:** MIRIAM GOCHIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $178,750
- **Award type:** 5
- **Project period:** 2018-11-16 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824573

## Citation

> US National Institutes of Health, RePORTER application 9824573, Covalent capture of small molecule - gp41 complexes (5R21AI140904-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9824573. Licensed CC0.

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