TY - JOUR T1 - Pharmacological Characterization of the Spectrum of Antiviral Activity and Genetic Barrier to Drug Resistance of M2-S31N Channel Blockers JF - Molecular Pharmacology JO - Mol Pharmacol SP - 188 LP - 198 DO - 10.1124/mol.116.105346 VL - 90 IS - 3 AU - Chunlong Ma AU - Jiantao Zhang AU - Jun Wang Y1 - 2016/09/01 UR - http://molpharm.aspetjournals.org/content/90/3/188.abstract N2 - 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. ER -