title: Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus.
abstract: Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections.
authors: Influmedix Inc, 170 North Radnor-Chester Road, Suite 300, Radnor, Pennsylvania 19087, United States.
authors: Jizhou
authors: J
authors: Wang
authors: Chunlong
authors: C
authors: Ma
authors: Jun
authors: J
authors: Wang
authors: Hyunil
authors: H
authors: Jo
authors: Belgin
authors: B
authors: Canturk
authors: Giacomo
authors: G
authors: Fiorin
authors: Lawrence H
authors: LH
authors: Pinto
authors: Robert A
authors: RA
authors: Lamb
authors: Michael L
authors: ML
authors: Klein
authors: William F
authors: WF
authors: DeGrado
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000378:metabolism; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins