Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride
Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride
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DOI：
10.1124/mol.115.102731
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发表时间：
2016-08-01
影响因子：
3.6
通讯作者：
Fedida, David
中科院分区：
文献类型：
--
作者：
Jalily, Pouria H.;Eldstrom, Jodene;Fedida, David
对已批准的抗病毒药物具有耐药性的流感病毒的日益流行突出了对新的抗流感治疗剂的需求。在这里，我们描述的功能特性的阿替米洛利（HMA）衍生的化合物，抑制野生型和金刚烷耐药形式的流感病毒A M2离子通道。例如，6-（氮杂环庚烷-1-基）-N-甲脒基烟酰胺（9）抑制金刚烷胺敏感性M2电流的效力比金刚烷胺或HMA高3- 6倍（IC 50 = 0.2对0.6和1.3 μ M）。化合物9与金刚烷胺竞争M2抑制，分子对接模拟表明9在与金刚烷胺结合重叠的位点结合。此外，4 ′-（甲脒基氨基甲酰基）-2 ′，3-二硝基-[1，1 ′-联苯]-4-羧酸叔丁酯（27）对编码丝氨酸至天冬酰胺31突变（S31 N）的金刚烷敏感型和耐药型M2变体均有作用，其疗效优于金刚烷胺和HMA（IC 50分别为0.6 μ M和4.4 μ M）。9抑制编码野生型M2的流感病毒的体外复制（EC 50 = 2.3 mM），而27和4 '-（甲脒基氨基甲酰基）-2'，3-二硝基-[1，1 '-联苯]-4-羧酸叔丁酯（26）优先抑制编码M2（S31 N）的病毒（各自的EC 50 = 18.0和1.5 μ M）。这一发现表明，HMA衍生物可以被设计成抑制对金刚烷胺具有抗性的病毒。我们的研究突出了HMA衍生物作为耐药流感M2离子通道抑制剂的潜力。
The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)-derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotina-mide (9) inhibits amantadine-sensitive M2 currents with 3- to 6-fold greater potency than amantadine or HMA (IC50 = 0.2 vs. 0.6 and 1.3 mu M, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate (27) acts both on adamantane-sensitive and a resistant M2 variant encoding a serine to asparagine 31 mutation (S31N) with improved efficacy over amantadine and HMA (IC50 = 0.6 mu M and 4.4 mu M, respectively). Whereas 9 inhibited in vitro replication of influenza virus encoding wild-type M2 (EC50 = 2.3 mM), both 27 and tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate (26) preferentially inhibited viruses encoding M2(S31N) (respective EC50 = 18.0 and 1.5 mu M). This finding indicates that HMA derivatives can be designed to inhibit viruses with resistance to amantadine. Our study highlights the potential of HMA derivatives as inhibitors of drug-resistant influenza M2 ion channels.