Structural and energetic analysis of drug inhibition of the influenza A M2 proton channel

•Stable drug binding in the channel pore inhibits the influenza A M2 channel.•Mutations in M2 perturb drug binding stability.•Structural biology and molecular simulations guide drug design for mutant M2 channels.•The M2 pore-binding site can bind to inhibitors of varying sizes.

The type A influenza virus matrix protein 2 (M2) is a highly selective proton channel in the viral envelope. Because of its crucial role in viral infection and replication, the M2 channel has been a target of anti-influenza drugs. Due to the occurrence of drug-resistant mutations in the M2 channel, existing anti-influenza drugs that block the M2 channel, such as amantadine and rimantadine, have lost their efficacy against these mutant channels. Recent experimental and computational efforts have made great progress in understanding the drug resistance mechanisms of these mutations as well as designing novel drug candidates to block the mutant M2 channels. In this review, we briefly summarize the structural characteristics of the M2 channel, and then we discuss these recent studies on drug resistance and drug design of the mutant channels, focusing on the structures and energetics. We show that structural biology experiments and molecular modeling have led to the successful design of novel drugs targeting mutant M2 channels.