title: Discovery of Potent Antivirals against Amantadine-Resistant Influenza A Viruses by Targeting the M2-S31N Proton Channel.
abstract: Despite the existence of flu vaccines and small-molecule antiviral drugs, influenza virus infection remains a public health concern that warrants immediate attention. As resistance to the only orally bioavailable drug, oseltamivir, has been continuously reported, there is a clear need to develop the next-generation of anti-influenza drugs. We chose the influenza A virus M2-S31N mutant proton channel as the drug target to address this need as it is one of the most conserved viral proteins and persist in >95% of currently circulating influenza A viruses. In this study, we report the development of a late-stage diversification strategy for the expeditious synthesis of M2-S31N inhibitors. The channel blockage and antiviral activity of the synthesized compounds were tested in two-electrode voltage clamp assays and antiviral assays, respectively. Several M2-S31N inhibitors were identified to have potent M2-S31N channel blockage and micromolar antiviral efficacy against several M2-S31N-containing influenza A viruses.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007251:Influenza, Human / Q000821:virology*; D020125:Mutation, Missense; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: M2 proton channel; M2-S31N inhibitor; influenza A virus