Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.,European Journal of Pharmaceutical Sciences

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Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-05 , DOI: 10.1016/j.ejps.2019.105124
Rami Musharrafieh ₁ , Chunlong Ma ₁ , Jun Wang ₁

Affiliation

Influenza virus infections are a persistent threat to human health due to seasonal outbreaks and sporadic pandemics. Amantadine and rimantadine are FDA-approved influenza antiviral drugs and work by inhibiting the viral M2 proton channel. However, the therapeutic potential for the antiviral amantadine/rimantadine was curtailed by the emergence of drug-resistant mutations in its target protein M2. In this study, we identified four amantadine-resistant M2 mutants among avian and human influenza A H5N1 strains circulating between 2002 and 2019: the single S31N and V27A mutants, and the S31N/L26I and S31N/V27A double mutants. Herein, utilizing two-electrode voltage clamp (TEVC) assays, we screened a panel of structurally diverse M2 inhibitors against these single and double mutant channels. Three compounds 6, 7, and 15 were found to significantly block all three M2 mutants: M2-S31N, M2-S31N/L26I, and M2-S31N/V27A. Using recombinant viruses generated from reverse genetics, we further showed that these compounds also inhibited the replication of recombinant viruses harboring either the single S31N or double S31N/L26I and S31N/V27A mutants. This work represents the first example in developing antivirals by targeting the drug-resistant double mutants of M2 proton channels.

中文翻译：

从甲型流感病毒中发现了针对耐药性双重突变体M2-S31N / L26I和M2-S31N / V27A的M2通道阻滞剂。

由于季节性暴发和零星的大流行，流感病毒感染是对人类健康的持续威胁。金刚烷胺和金刚乙胺是FDA批准的流感抗病毒药物，可通过抑制病毒M2质子通道发挥作用。但是，抗病毒金刚烷胺/金刚烷胺的治疗潜力因其靶蛋白M2中出现耐药性突变而受到限制。在这项研究中，我们在2002年至2019年之间传播的禽和人类A型流感H5N1菌株中鉴定了四个耐金刚烷胺的M2突变体：单个S31N和V27A突变体以及S31N / L26I和S31N / V27A双重突变体。在这里，我们利用两电极电压钳（TEVC）分析，筛选了针对这些单突变和双突变通道的一组结构多样的M2抑制剂。三种化合物6，7，发现15和15可显着阻断所有三个M2突变体：M2-S31N，M2-S31N / L26I和M2-S31N / V27A。使用从逆向遗传学产生的重组病毒，我们进一步表明，这些化合物还抑制了携带单个S31N或双重S31N / L26I和S31N / V27A突变体的重组病毒的复制。这项工作代表了针对M2质子通道的耐药双重突变体开发抗病毒药物的第一个例子。

更新日期：2019-11-05

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