Design and Pharmacological Characterization of Inhibitors of Amantadine-Resistant Mutants of the M2 Ion Channel of Influenza A Virus
Design and Pharmacological Characterization of Inhibitors of Amantadine-Resistant Mutants of the M2 Ion Channel of Influenza A Virus
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DOI：
10.1021/bi9014488
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发表时间：
2009-12-22
期刊：
影响因子：
2.9
通讯作者：
Pinto, Lawrence H.
中科院分区：
文献类型：
--
作者：
Balannik, Victoria;Wang, Jun;Pinto, Lawrence H.
甲型流感病毒的A/M2质子通道是抗流感药物金刚烷胺和金刚乙胺的靶点，其有效性因A/M2通道孔中自然存在的点突变体而降低，其中最常见的是S31N、V27A和L26F。我们合成并表征了一系列化合物的性质，这些化合物最初来源于a /M2抑制剂BL-1743。从这些研究中发现的一种先导化合物，螺旋[5.5]十一烷-3胺，在体外是野生型A/M2通道和L26F和V27A突变离子通道的有效抑制剂，并且在斑块减少试验中也抑制携带这些突变的重组突变病毒的复制。已知在A/M2通道孔内结合的BL-1743和金刚烷胺之间的抑制动力学差异被用来证明这些化合物之间的竞争，与金刚烷胺在通道孔内结合的结论一致。所有这些化合物的抑制作用都是电压无关的，这表明它们的带电基团位于孔的n端，在选择性过滤器定义跨膜电位发生的区域之前。这些发现不仅有助于确定M2通道阻断药物的结合位置和机制，而且还证明了在许多金刚烷胺耐药突变体中发现针对该结合位点的新抑制剂的可行性。
The A/M2 proton channel of influenza A virus is a target for the anti-influenza drugs amantadine and rimantadine, whose effectiveness was diminished by the appearance of naturally occurring point mutants in the A/M2 channel pore, among which the most common are S31N, V27A, and L26F. We have synthesized and characterized the properties of a series of compounds, originally derived from the A/M2 inhibitor BL-1743. A lead compound emerging from these investigations, spiro[5.5]undecan-3-amine, is an effective inhibitor of wild-type A/M2 channels and L26F and V27A mutant ion channels in vitro and also inhibits replication of recombinant mutant viruses bearing these mutations in plaque reduction assays. Differences in the inhibition kinetics between BL-1743, known to bind inside the A/M2 channel pore, and amantadine were exploited to demonstrate competition between these compounds, consistent with the conclusion that amantadine binds inside the channel pore. Inhibition by all of these compounds was shown to be voltage-independent, suggesting that their charged groups are within the N-terminal half of the pore, prior to the selectivity filter that defines the region over which the transmembrane potential occurs. These findings not only help to define the location and mechanism of binding of M2 channel-blocking drugs but also demonstrate the feasibility of discovering new inhibitors that target this binding site in a number of amantadine-resistant mutants.