Pharmacological Characterization of the Spectrum of Antiviral Activity and Genetic Barrier to Drug Resistance of M2-S31N Channel Blockers.

摘要: Adamantanes (amantadine and rimantadine) are one of the two classes Food Drug Administration–approved antiviral drugs used for prevention treatment influenza A virus infections. They inhibit viral replication by blocking wild-type (WT) M2 proton channel, thus preventing uncoating. However, their use was discontinued due to widespread drug resistance. Among a handful drug-resistant mutants, M2-S31N is predominant mutation persists in more than 95% currently circulating strains. We recently designed inhibitors, S31N-specific inhibitors S31N/WT dual which represented N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine (WJ379) N-[(5-bromothiophen-2-yl)methyl]adamantan-1-amine (BC035), respectively. activities against viruses genetic barrier resistance unknown. In this report, we evaluated therapeutic potential these (WJ379 BC035) profiling efficacy multidrug-resistant viruses, vitro barrier, synergistic effect with oseltamivir. found that were active several resistant or both anti-influenza drugs. addition, display higher amantadine. The WJ379 also oseltamivir carboxylate. Overall, results reaffirm promising candidates warrant further development.