# Understanding Envelope Function in HIV-1 Infection: The Design, Synthesis and Validation of Small Molecule HIV-1 Env Inhibitors

> **NIH NIH P01** · DREXEL UNIVERSITY · 2021 · $303,360

## Abstract

Understanding Env Function in HIV-1 Infection:
The Design, Synthesis and Validation of Small Molecule HIV-1 Env Inhibitors
Project 3: Summary:
The Central Goal of this Program Project (P0-1-GM-06550) comprises the identification and understanding of
the functional states of the HIV-1 envelope (Env) trimer: (a) in the standalone virion; (b) during the HIV-1 cell
entry process; and (c) during the process of antibody dependent cellular cytotoxicity (ADCC) of HIV-1 infected
cells. Specifically we propose to design, synthesize and validate small molecules that bind to the HIV-1 Env
glycoproteins (gp120 and gp41), and in turn modulate the HIV-1 Env functional states. Such an objective will
require the accumulation of knowledge regarding the nature and function of the Env trimer at the highest
possible level of atomic resolution. The derived understanding in turn will permit the design and synthesis of
effective HIV-1 virion inactivators, cell entry inhibitors and ADCC sensitizers of HIV-1 infected cells, which hold
the promise for both the prevention and eradication of HIV/AIDS. The specific targeted compounds,
anticipated to bind the CD4 binding pocket, to other regions of the gp120 subunit and/or to the gp41 subunit,
will arise through the close collaborative use of smFRET studies (Program 1), crosslinking-mass spectrometry,
inhibitor binding bioassay data (Projects 2, 4 and Core B), high-resolution X-ray/cryoEM structures (Project 5
and collaborator Pamela Björkman) and computational modeling (Core A). Importantly, the recent
technological advances in cryoEM and smFRET trimer visualization, in conjunction with biological
measurements (Projects 1, 2, 4 and Core B), will permit elucidation of the specific effects that small molecule
Env modulators have on the function of the HIV-1 Env. As such, the efforts of the P01 will clearly aid in the
design and validation of new pharmacological tactics to address the AIDS pandemic.
 Project 3, The Synthetic Thrust of this Program Project, will focus specifically on the Program Project
goals by developing and validating new classes of small molecules that interact uniquely with the HIV-1 Env
trimer (gp120 and gp41), thereby providing insights into the landscape of Env conformations (i.e., Env states)
and their biological implications. The close collaboration that has and will continue to occur between each of
the five Program Projects and two Cores will clearly enhance the discovery, design, and validation of more
highly functional, broad spectrum small molecule inhibitors/ADDC sensitizers of HIV-1 infected cells, as well as
lead to labeled probes to identify, stabilize and/or modulate the important Env conformational changes leading
to cell entry and/or infected cell eradication. Thus, through high throughput screens, computational modeling,
design, and synthesis, along with structural analysis (smFRET/crystal/cryoEM) and bioassay/binding validation
measurements, Project 3 will play a central, highly focused ro...

## Key facts

- **NIH application ID:** 10240543
- **Project number:** 5P01AI150471-25
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Amos B Smith
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $303,360
- **Award type:** 5
- **Project period:** 1997-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240543

## Citation

> US National Institutes of Health, RePORTER application 10240543, Understanding Envelope Function in HIV-1 Infection: The Design, Synthesis and Validation of Small Molecule HIV-1 Env Inhibitors (5P01AI150471-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240543. Licensed CC0.

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