# Inhibition of Resistant Variants of HIV Protease

> **NIH NIH U01** · GEORGIA STATE UNIVERSITY · 2020 · $345,420

## Abstract

Inhibition of Resistant Variants of HIV Protease
HIV/AIDS is a serious pandemic with over 36 million infected people. Antiviral drug therapy
has decreased the mortality, although the number of new infections remains about 2
million per year. However, the genetic diversity and high mutability of HIV pose a critical
challenge for continued efficacy of drugs and development of effective vaccines. Hence,
there is urgent need for new therapies to overcome the problem of drug-resistance. We
are tackling this challenge by studying the important drug target of HIV protease. Clinical
resistance arises even for the potent antiviral inhibitor darunavir. Our structural analyses
have identified distinct molecular mechanisms for resistance including mutations that: 1)
decrease protease interactions with inhibitors; 2) decrease the enzyme stability; or 3)
influence the dynamics. In the last project period, our X-ray structures have guided the
design of novel inhibitors 10-fold more effective than darunavir against highly resistant
proteases. We have developed algorithms to predict resistance from genotype sequences
and have identified representative mutants with high level resistance. We propose to
identify common mechanism for resistance and apply these insights to design and assess
new inhibitors. These multidisciplinary studies leverage the expertise, unique resources
and novel approaches developed in the PIs groups together with an established set of
collaborators to integrate computational, X-ray crystallographic, biochemical and
biophysical techniques with inhibitor design, chemical synthesis, and virology studies. The
expected outcomes will be 1) accurate predictions for resistance, 2) discovery of novel
and conserved molecular mechanisms for resistance, and 3) new antiviral inhibitors for
resistant HIV infections.

## Key facts

- **NIH application ID:** 9957016
- **Project number:** 5U01AI150461-22
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** ROBERT Wilson HARRISON
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,420
- **Award type:** 5
- **Project period:** 1997-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957016

## Citation

> US National Institutes of Health, RePORTER application 9957016, Inhibition of Resistant Variants of HIV Protease (5U01AI150461-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957016. Licensed CC0.

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