# Computer-Aided Design of Anti-HIV Drugs

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

Project Summary/Abstract
 The purpose of the research program is to discover new anti-HIV drugs that are potent, safe, easily
administered, and long-acting. The approach combines state-of-the-art technology for molecular design,
synthetic organic chemistry, biological assaying, and crystallographic determination of structures of the
designed molecules bound to their protein target. The PI's research program emphasizes fundamental
advances in the development of software and methodology for drug design, detailed modeling of protein-ligand
binding, and organic synthesis. The PI's group has developed computational tools to speed lead optimization
for potency, while being mindful of the need for desirable pharmacological properties. For the HIV work,
collaborations with scientist in the Yale School of Medicine provide the determinations of biological activity in
vitro, in human T-cells, and in humanized mouse models, as well as macromolecular structures through protein
crystallography.
 The specific focus is the discovery of inhibitors of HIV-1 reverse transcriptase (HIV-RT), which are a central
component of highly active antiretroviral therapy (HAART). The previous grant period witnessed striking
advances for our development of the catechol diether series of non-nucleoside inhibitors of HIV-RT.
Compounds have been discovered that show remarkable potency, no cytotoxicity, no off-target activity,
excellent pharmacological properties, and efficacy in a humanized mouse model of HIV-1 infection. From our
extensive crystallographic and modeling studies, thorough knowledge of the binding site has also led to an
important new direction of developing the first covalent inhibitors of HIV-RT (CRTIs). We initially targeted the
clinically problematic Tyr181Cys RT variants and designed CRTIs that completely knock out activity of the
resistant mutants. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme
inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell
assays. The CRTIs were also shown to be selective for Cys181 and have lower cytotoxicity than the approved
drugs efavirenz and rilpivirine. Our compounds are rare examples of targeted covalent allosteric inhibitors,
which have enhanced potential for low dosage, low toxicity, and extended duration of action. Extensive
discovery, characterization, and development of CRTIs targeting both wild type and resistant forms of HIV-1
are the focus for the next grant period. CRTIs are a new class of anti-HIV agents with potentially profound
therapeutic impact.

## Key facts

- **NIH application ID:** 10113507
- **Project number:** 5R01AI044616-23
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** William L. Jorgensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 1999-01-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113507

## Citation

> US National Institutes of Health, RePORTER application 10113507, Computer-Aided Design of Anti-HIV Drugs (5R01AI044616-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10113507. Licensed CC0.

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