# Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry

> **NIH NIH P01** · DREXEL UNIVERSITY · 2021 · $1,902,856

## Abstract

OVERALL PROGRAM PROJECT SUMMARY
The goal of this Program Project is the discovery, design, synthesis, optimization and validation of small molecule
antagonists of the HIV-1 envelope (Env) trimer, combined with the definition of their molecular, virological and
cellular mechanisms of action to identify potential preventive and therapeutic approaches to attack the HIV-
1/AIDS pandemic. The HIV-1 Env trimer is the only virus-specific protein on both the exposed surface of HIV-1
virions and on HIV-1 infected cells, and as such is a crucial first target for prevention and intervention of virus
infection. Compounds that can bind with sufficient affinity, specificity and breadth to sequence-conserved and
functional centers on Env should be able to inhibit, inactivate, and/or prematurely activate Env on the virus and
on infected cells. In so doing, such compounds could block both cell infection and the formation of new infectious
viruses, and prime infected cells for eradication. Major advancements have been made in our Program Project
during the past 5 years to identify small molecule HIV-1 Env inhibitors that [1] allosterically or competitively block
HIV-1 cell receptor interactions and cell infection; [2] irreversibly inactivate both the virus and virus-infected cells;
and [3] sensitize cells to antibody-mediated immune responses. This progress opens up important opportunities
to identify and explore the fundamental mechanisms of Env antagonism. Our progress going forward in
developing small molecule inhibitors will be greatly facilitated by a deepening understanding of conformational
states, dynamics and high-resolution structures of the HIV-1 Env trimer, as well as an understanding of how this
molecular machine is activated to mediate fusion between viral and cellular membranes. In turn, the
understanding of Env trimer structure and dynamics will be aided by small molecule inhibitors, developed by our
Program Project, that function as chemical probes to inhibit, entrap or activate specific conformational states.
The discovery, design, synthesis, optimization and validation of small molecules will enhance the identification
of preventive, therapeutic and eradication interventions for HIV-1/AIDS. We will pursue a comprehensive
mechanistic approach to investigate HIV-1 Env antagonism. To accomplish this, 7 investigators organized in 5
projects and 3 cores will pursue a multi-disciplinary integrated and synergistic approach. Knowing that no single
group can succeed alone, the program has established a highly collaborative and efficient infrastructure, with an
atmosphere where ideas are discussed early, new findings exchanged quickly, and the most effective strategies
validated in order to fulfill the research goals. This Program Project will build both on an experienced group of
investigators as well as the two new investigators to respond to new developments and challenges.

## Key facts

- **NIH application ID:** 10240536
- **Project number:** 5P01AI150471-25
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** IRWIN M CHAIKEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,902,856
- **Award type:** 5
- **Project period:** 1997-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240536

## Citation

> US National Institutes of Health, RePORTER application 10240536, Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry (5P01AI150471-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10240536. Licensed CC0.

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