Novel Mechanisms of SARS-CoV-2 Drug Resistance and Rational Design of Anti-Resistant Antivirals

Antiviral drug resistance in SARS-CoV-2 is increasingly limiting treatment efficacy. Four recent studies have revealed two key resistance mechanisms: (1) Mutations in the main protease (Mpro)—including E166V, E166A, and S144-series variants—disrupt drug binding or active-site conformation, reducing nirmatrelvir efficacy. (2) The proofreading exoribonuclease (ExoN) removes incorporated nucleoside analogues (e.g., bemnifosbuvir, sofosbuvir), conferring resistance. Guided by structural and pharmacological insights, three effective countermeasures have been established: structure-based optimization of Mpro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies. These advances provide a solid framework for developing next-generation antivirals to combat emerging resistant SARS-CoV-2 variants.