Structure-Based Design of Covalent SARS-CoV‑2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants.

ABSTRACT: The COVID-19 pandemic spurred the rapid development of nirmatrelvir, a main protease (M^pro) inhibitor now widely prescribed as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing use has raised concerns about drug resistance. Resistance selection studies have identified multiple M^pro mutations, with E166V emerging as a particularly resistant variant. Sequencing data from COVID-19 patients confirms E166V as a clinically relevant mutation, and importantly, this substitution also confers cross-resistance to several next-generation M^pro inhibitors under development. In response, this study reports the rational design of inhibitors active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, Jun13698, shows potent inhibition

SUBMITTER: Cai Z 

PROVIDER: S-EPMC12848695 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature