Award
National Institute of Allergy and Infectious Diseases 5R21AI191052-02
Comprehensive analysis of epistasis in drug resistance potential of Mpro from SARS-CoV-2
Recipient
University of Massachusetts Medical School Worcester
Award Amount
$209,375.00
Ceiling
$209,375.00
Awarded
February 06, 2026
Identifier
5R21AI191052-02
The award funds research to analyze how combinations of mutations in SARS-CoV-2 Mpro affect drug resistance and enzyme activity, focusing on the drug nirmatrelvir in Paxlovid.
Description
This project aims to systematically investigate a critical, but poorly understood aspect of drug resistance evolution: the interdependence of mutations that disrupt drug binding (usually also decreasing enzyme activity) and compensatory mutations that increase enzyme activity. The study focuses on mutations in Mpro from SARS-CoV-2 that disrupt binding to nirmatrelvir, the active component in Paxlovid, an effective COVID-19 treatment. Using a yeast screen for Mpro activity, the project will analyze how combinations of mutations impact enzyme activity and drug disruption, providing insights into the evolution of drug resistance.