# Structural and Biochemical Effects of Capsid-targeting Molecules on HIV-1 Capsid Assembly

> **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $47,694

## Abstract

Abstract
HIV infection impacts over 37 million individuals, with over 2/3 of these patients receiving antiretroviral therapies
(ART). ART is sustained for a patient’s life and can lead to the emergence of drug-resistant HIV-1. To combat
drug-resistance, an improved and diverse set of antiretrovirals are needed for clinical use. To this extent, the
HIV-1 capsid is an excellent target for antiretroviral therapies as it has numerous, essential roles throughout the
HIV-1 replication cycle. Compounds that target the capsid protein (CA), known as capsid effectors (CEs), offer
a novel class of HIV-1 antivirals for potential clinical use. One CE with marked success is lenacapavir, developed
by Gilead Sciences. Lenacapavir is exceptionally potent, however, early results show treatment with lenacapavir
can cause the emergence of antiviral-resistant HIV-1. Our lab has previously reported highly potent antiretrovirals
that target the same site as lenacapavir, within the FG-binding pocket. Compounds that bind to the FG-binding
pocket of CA mimic a conserved phenylalanine-glycine (FG) dipeptide motif found in many host factors reported
to bind CA. Here, I will characterize structural changes to the HIV-1 capsid upon treatment with highly potent
CEs that bind the FG-binding pocket and calculate the biochemical parameters of CA•CE interactions for this
class of antiretroviral therapeutics. The nature of CA•CE interactions will be assessed in wild-type (WT) and
drug-resistant viruses to further our understanding of antiviral resistance. Electron microscopy (EM) will be used
to visualize drug-resistant capsid assemblies and discern structural changes relative to WT assemblies (AIM 1).
Rates of capsid assembly and changes to thermal stability upon drug-treatment will be calculated using assays
designed to probe CA•CA interactions (AIM 2). These aims will study mutations that confer antiviral-resistance
and results will be compared to WT CA to identify those with similar phenotypes and therefore higher risks of
resistance. Further, CA•CE biochemical parameters of affinity and dissociation rates will be solved by label-free
optical detection. This study will further our mechanistic understanding of compounds that bind to the FG-binding
pocket of CA. Overall, these results will enable future research to strategically improve antiretrovirals, aiming to
combat the HIV-1 epidemic.

## Key facts

- **NIH application ID:** 10619783
- **Project number:** 1F31AI174951-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** WILLIAM MICHAEL MCFADDEN
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $47,694
- **Award type:** 1
- **Project period:** 2022-12-29 → 2026-12-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619783

## Citation

> US National Institutes of Health, RePORTER application 10619783, Structural and Biochemical Effects of Capsid-targeting Molecules on HIV-1 Capsid Assembly (1F31AI174951-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10619783. Licensed CC0.

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