# Design of inhibitors targeted to the CD4 binding site on HIV-1 gp120

> **NIH NIH R01** · NEW YORK BLOOD CENTER · 2020 · $792,805

## Abstract

Project Summary/Abstract
 The HIV-1 envelope glycoprotein gp120 plays a critical role in mediating viral entry into host cells and has
been validated as a prime target for small-molecule drugs and vaccine development, yet no drugs against
gp120 have been approved by the US Food and Drug Administration (FDA) to date. Therefore, there is a
critical need to develop novel drugs against this target. Our group made significant headway in filling this
critical need by developing a new class of HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120.
This renewal application builds on the in-depth knowledge gained during the current funding cycle from the
extensive X-ray structure, synthesis, as well as the antiviral activity and toxicity data and in vitro ADMET
profiles of this class of novel entry inhibitor. The development of novel therapeutics will aid in increasing the
number of new and novel drugs available, especially for the treatment-experienced patients, who have limited
treatment options and will extend the scope of combination therapy. This highly coordinated effort will further
our goal of developing potent inhibitors for moving to the next phase of preclinical assessments in animals and
for selecting two to three inhibitors as potential clinical candidates. Our long-term goal is to develop novel,
highly potent, and less toxic oral anti-HIV drugs, which are expected to serve as a new arsenal for combination
therapy, especially for treatment-experienced patients. We will achieve our goals by addressing four highly
coordinated, hypothesis-driven specific aims: 1. Optimize next-generation HIV-1 entry antagonists by structure-
based design and comprehensive medicinal chemistry. 2. Evaluate the antiviral potency, toxicity, mechanism
of action, and drug resistance. 3. Measure the binding thermodynamics and determine the X-ray structure of
the most potent entry inhibitors with (a) monomeric gp120 and (b) trimeric gp120. 4. Evaluate the in vitro
ADMET and in vivo pharmacokinetics (PK) in laboratory animals.

## Key facts

- **NIH application ID:** 9852412
- **Project number:** 5R01AI104416-08
- **Recipient organization:** NEW YORK BLOOD CENTER
- **Principal Investigator:** Asim K Debnath
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $792,805
- **Award type:** 5
- **Project period:** 2013-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852412

## Citation

> US National Institutes of Health, RePORTER application 9852412, Design of inhibitors targeted to the CD4 binding site on HIV-1 gp120 (5R01AI104416-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852412. Licensed CC0.

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