Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.
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DOI：
10.1021/jm101334y
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发表时间：
2011-04-28
影响因子：
7.3
通讯作者：
Vázquez S
中科院分区：
文献类型：
--
作者：
Duque MD;Ma C;Torres E;Wang J;Naesens L;Juárez-Jiménez J;Camps P;Luque FJ;DeGrado WF;Lamb RA;Pinto LH;Vázquez S
金刚烷胺抑制甲型流感病毒的M2质子通道，但其临床应用受到金刚烷胺耐药病毒株迅速出现的限制。我们已经合成并表征了一系列的多环化合物，设计为金刚烷胺的缩环或扩环类似物。使用双电极电压钳（TEV）测定法在非洲爪蟾卵母细胞中测量野生型（wt）M2通道和A/M2-S31 N和A/M2-V27 A突变体离子通道的抑制。几个双降金刚烷和降金刚烷衍生物抑制wt离子通道。化合物结合到由Val 27、Ala 30和Ser 31描绘的主要位点，尽管环扩张限制了结合位点中的定位。发现只有最小的类似物8抑制S31 N突变体离子通道。用携带wt M2蛋白的A/H3 N2流感病毒进行空斑减少试验，证实了通过TEV测定获得的结构-活性关系。
Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogs of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30 and Ser31, though ring-expansion restricts the positioning in the binding site. Only the smallest analog 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.
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影响因子：
3.5
作者：
Camps P;Duque MD;Vázquez S;Naesens L;De Clercq E;Sureda FX;López-Querol M;Camins A;Pallàs M;Prathalingam SR;Kelly JM;Romero V;Ivorra D;Cortés D
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
6.4
作者：
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通讯作者：
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