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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K~+ channels
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Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K~+ channels

机译：工程化的特异性和高亲和力抑制剂，用于内向整流子K〜+通道的亚型

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摘要

Inward-rectifier K~+ (Kir) channels play many important biological roles and are emerging as important therapeutic targets. Subtype-specific inhibitors would be useful tools for studying the channels' physiological functions. Unfortunately, available K~+ channel inhibitors generally lack the necessary specificity for their reliable use as pharmacological tools to dissect the various kinds of K~+ channel currents in situ. The highly conserved nature of the inhibitor targets accounts for the great difficulty in finding inhibitors specific for a given class of K~+ channels or, worse, individual subtypes within a class. Here, by modifying a toxin from the honey bee venom, we have successfully engineered an inhibitor that blocks Kir1 with high (1 nM) affinity and high ( > 250-fold) selectivity over many commonly studied Kir subtypes. This success not only yields a highly desirable tool but, perhaps more importantly, demonstrates the practical feasibility of engineering subtype-specific K~+ channel inhibitors.
机译：内向整流子K〜+（Kir）通道起着许多重要的生物学作用，并且正在成为重要的治疗靶点。亚型特异性抑制剂将是研究通道的生理功能的有用工具。不幸的是，可用的K +通道抑制剂通常缺乏可靠的用途，因为它们不能可靠地用作药理学工具来原位解剖各种K +通道电流。抑制剂靶标的高度保守的性质导致难以找到针对给定类别的K +通道或更坏的类别中的个体亚型的抑制剂。在这里，通过修饰蜜蜂毒液中的毒素，我们已经成功设计出了一种抑制剂，与许多常用的Kir亚型相比，它具有高（1 nM）亲和力和高（> 250倍）选择性的Kir1阻断剂。这一成功不仅产生了非常理想的工具，而且也许更重要的是证明了工程化亚型特异性K +通道抑制剂的实际可行性。

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