Investigation of the Drug Resistance Mechanism of M2-S31N Channel Blockers through Biomolecular Simulations and Viral Passage Experiments.

ABSTRACT: Recent efforts in drug development against influenza A virus (IAV) M2 proton channel S31N mutant resulted in conjugates of amantadine linked with aryl head heterocycles. To understand the mechanism of drug resistance, we chose a representative M2-S31N inhibitor, compound 3, as a chemical probe to identify resistant mutants. To increase the possibility of identifying novel resistant mutants, serial viral passage experiments were performed with multiple strains of H1N1 and H3N2 viruses in different cell lines. This approach not only identified M2 mutations around the drug-binding site, including the pore-lining residues (V27A, V27F, N31S, and G34E) and an interhelical residue (I32N), but also a new allosteric mutation (R45H), in addition to L46P previously identified, located at the C

SUBMITTER: Musharrafieh R 

PROVIDER: S-EPMC7432665 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature