title: Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel.
abstract: With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses; thus, it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2(+)CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in-depth preclinical pharmacology.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.|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, The University of Arizona , Tucson, Arizona 85721, United States.|BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.|BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D054328:Proton Pump Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D054328:Proton Pump Inhibitors; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins