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

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 show...

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Vydané v:	Proceedings of the National Academy of Sciences - PNAS Ročník 110; číslo 4; s. 1315
Hlavní autori:	Wang, Jun, Wu, Yibing, Ma, Chunlong, Fiorin, Giacomo, Wang, Jizhou, Pinto, Lawrence H, Lamb, Robert A, Klein, Michael L, Degrado, William F
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 22.01.2013
Predmet:	Amantadine - analogs & derivatives Amantadine - chemical synthesis Amantadine - chemistry Amantadine - pharmacology Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Binding Sites Drug Design Drug Resistance, Viral - genetics Genes, Fungal Humans Influenza A virus - chemistry Influenza A virus - drug effects Influenza A virus - genetics Models, Molecular Mutation Nuclear Magnetic Resonance, Biomolecular Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Recombinant Proteins - genetics Structure-Activity Relationship Viral Matrix Proteins - antagonists & inhibitors Viral Matrix Proteins - chemistry Viral Matrix Proteins - genetics
ISSN:	1091-6490, 1091-6490
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Shrnutí:	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 chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1216526110