# Impact of Env conformational regulation on HIV-1 sensitivity to small-molecule entry inhibitors

> **NIH NIH P01** · DREXEL UNIVERSITY · 2021 · $344,899

## Abstract

Project 2: Sodroski – Impact of Env conformational regulation on HIV-1 sensitivity to small-molecule
entry inhibitors
SUMMARY
 The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer binds to host receptors,
CD4 and CCR5/CXCR4, and mediates the entry of the virus into the target cell. As a result of receptor binding,
the Env trimer undergoes large-scale conformational changes from the unliganded state (State 1) to more
“open” conformations (States 2 and 3). Small-molecule inhibitors of HIV-1 entry bind the Env trimer and either
block conformational changes or prematurely trigger non-productive conformational changes. Thus, small-
molecule entry inhibitors serve as useful probes of Env trimer conformation. In this project, we will utilize
crosslinking and mass spectrometry to evaluate the conformation of HIV-1 Env in the absence and presence of
small molecules. We will evaluate the impact of natural HIV-1 variation on virus sensitivity to CD4-mimetic
compounds. We will investigate the Env binding site and mechanism of action of another small-molecule
HIV-1 entry inhibitor, MF275. MF275 inhibits infection of some HIV-1 strains, but enhances the infection of
CD4-negative target cells by other HIV-1 strains. The CD4-mimetic compounds and MF275 bind to distinct
sites on the HIV-1 Env trimer, and prematurely activate Env by driving it from State 1 into States 2 and 3. In
addition to these more focused aims, we will evaluate the Env conformational effects and antiviral potency,
breadth and specificity of novel HIV-1 entry inhibitors developed in Projects 3 and 4 of this Program. An
understanding of the impact of HIV-1 Env conformational variation on the antiviral activity of small-molecule
inhibitors will assist efforts to improve their efficacy.

## Key facts

- **NIH application ID:** 10240542
- **Project number:** 5P01AI150471-25
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** JOSEPH G SODROSKI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,899
- **Award type:** 5
- **Project period:** 1997-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240542

## Citation

> US National Institutes of Health, RePORTER application 10240542, Impact of Env conformational regulation on HIV-1 sensitivity to small-molecule entry inhibitors (5P01AI150471-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10240542. Licensed CC0.

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