Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus.

ABSTRACT: The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side ch

SUBMITTER: Wang J 

PROVIDER: S-EPMC3557100 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature