Department of Chemistry and Center for Neuroscience Research, University at Albany, State University of New York, Albany, New York 12222, USA.
Biochemistry. 2010 Jul 13;49(27):5790-8. doi: 10.1021/bi100690k.
Inhibitors of AMPA receptors are useful as biochemical probes for structure-function studies and as drug candidates for a number of neurological disorders and diseases. Here we report the identification of an RNA inhibitor or aptamer by an in vitro evolution approach. Using a laser-pulse photolysis technique, we further characterized the mechanism of inhibition of this aptamer on the AMPA receptor channel-opening rate process in the microsecond-to-millisecond time domain. Our results show that the aptamer we isolated is a noncompetitive inhibitor that selectively inhibits the open-channel conformation of AMPA receptors with nanomolar affinity. The potency and the selectivity of this noncompetitive aptamer rival those of small molecule inhibitors. Our results therefore demonstrate the utility of this approach in developing water-soluble, highly potent, and conformation-selective noncompetitive inhibitors of AMPA receptors.
AMPA 受体抑制剂可用作生化探针，用于研究结构-功能关系，也可用作多种神经紊乱和疾病的药物候选物。在此，我们报告了一种通过体外进化方法鉴定的 RNA 抑制剂或适体。我们进一步使用激光脉冲光解技术，在微秒到毫秒的时间域内对这种适体在 AMPA 受体通道开启速率过程中的抑制机制进行了表征。我们的结果表明，我们分离出的适体是一种非竞争性抑制剂，它以纳摩尔亲和力选择性地抑制 AMPA 受体的开放通道构象。这种非竞争性适体的效力和选择性可与小分子抑制剂相媲美。因此，我们的结果证明了这种方法在开发水溶性、高效能和构象选择性的 AMPA 受体非竞争性抑制剂方面的实用性。
