# Design & Synthesis of Nonpeptide Protease Inhibitors

> **NIH NIH R37** · PURDUE UNIVERSITY · 2020 · $484,067

## Abstract

The discovery of HIV, the etiological agent for AIDS , led to the identification of a number of biochemical
targetstocombatthisdevastatingdisease.Amongthem,therapeuticinhibitionofaproteolyticenzyme,HIV-
1 protease, emerged as a critical drug-development target. Subsequent design and discovery of protease
inhibitors (Pis) and their introduction into the highly active antiretroviral therapy (HAART) , marked the
beginning of a new era of management of HIV-1 infection and AIDS. HAART significantly improved the
quality of life and life expectancy of patients. There is no cure for HIV/AIDS and long-term treatment has
posed a serious challenge because of the emergence of multidrug-resistant HIV-1 variants. The majority of
patients who initially achieved favorable viral suppression to undetectable levels experienced treatment
failure. These drug-resistant HIV strains can be transmitted, raising further uncertainty with respect to future
treatment options. In addition, Pis are faced with a number of serious limitations including, major toxicity,
tolerance, and adherence to complex medical regimens.
Our collaborative research efforts to combat drug resistance, led to the development of darunavir which was
first approved for treatment against drug-resistant HIV in June, 2006, and then received full approval for all
HIV/AIDS patients including pediatric patients in December, 2008. While darunavir has become a front line
therapy against HIV/AIDS, it is far from ideal as a long-term treatment option . During this project period,
based upon X-ray crystal structures of complexes of darunavir or other Pis with HIV-1 protease, we designed
and synthesized a diverse class of potent Pis with marked antiviral activity, and excellent drug-resistance
profiles against multidrug-resistant HIV-1 strains. We have also developed tools and important 'backbone
binding' design concepts to combat drug-resistance. In our ongoing research, we have integrated our
expertise in structure-based design and synthesis with strong talents in protein-ligand X-ray crystallography
and in-depth virus and cell biological studies and created a number of exceptionally potent nonpeptide HIV-1
protease inhibitors with clinical potential.

## Key facts

- **NIH application ID:** 9999394
- **Project number:** 5R37AI150466-26
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** ARUN K GHOSH
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $484,067
- **Award type:** 5
- **Project period:** 1995-09-01 → 2023-05-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999394

## Citation

> US National Institutes of Health, RePORTER application 9999394, Design & Synthesis of Nonpeptide Protease Inhibitors (5R37AI150466-26). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9999394. Licensed CC0.

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