title: Pharmacological Characterization of the Spectrum of Antiviral Activity and Genetic Barrier to Drug Resistance of M2-S31N Channel Blockers.
abstract: Adamantanes (amantadine and rimantadine) are one of the two classes of Food and Drug Administration-approved antiviral drugs used for the prevention and treatment of influenza A virus infections. They inhibit viral replication by blocking the wild-type (WT) M2 proton channel, thus preventing viral uncoating. However, their use was discontinued due to widespread drug resistance. Among a handful of drug-resistant mutants, M2-S31N is the predominant mutation and persists in more than 95% of currently circulating influenza A strains. We recently designed two classes of M2-S31N inhibitors, S31N-specific inhibitors and S31N/WT dual inhibitors, which are represented by N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine (WJ379) and N-[(5-bromothiophen-2-yl)methyl]adamantan-1-amine (BC035), respectively. However, their antiviral activities against currently circulating influenza A viruses and their genetic barrier to drug resistance are unknown. In this report, we evaluated the therapeutic potential of these two classes of M2-S31N inhibitors (WJ379 and BC035) by profiling their antiviral efficacy against multidrug-resistant influenza A viruses, in vitro drug resistance barrier, and synergistic effect with oseltamivir. We found that M2-S31N inhibitors were active against several influenza A viruses that are resistant to one or both classes of Food and Drug Administration-approved anti-influenza drugs. In addition, M2-S31N inhibitors display a higher in vitro genetic barrier to drug resistance than amantadine. The antiviral effect of WJ379 was also synergistic with oseltamivir carboxylate. Overall, these results reaffirm that M2-S31N inhibitors are promising antiviral drug candidates that warrant further development.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, University of Arizona, Tucson, Arizona.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, University of Arizona, Tucson, Arizona.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, University of Arizona, Tucson, Arizona junwang@pharmacy.arizona.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D005814:Genes, Viral; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D050505:Mutant Proteins / Q000378:metabolism*; D053139:Oseltamivir / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D012692:Serial Passage; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D049990:Membrane Transport Modulators; D050505:Mutant Proteins; D053139:Oseltamivir; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins