公开(公告)号：US20130289100A1

公开(公告)日：2013-10-31

申请号：US13810572

申请日：2011-07-15

申请人： Li Niu ,  Zhen Huang ,  Jae Seon Park

发明人： Li Niu ,  Zhen Huang ,  Jae Seon Park

IPC分类号： C12N15/115

CPC分类号： C12N15/115 ,  C12N15/111 ,  C12N15/1138 ,  C12N2310/16 ,  C12N2310/322 ,  C12N2310/3533 ,  C12N2320/13

摘要： Inhibitors of AMPA-type glutamate ion channels are useful as biochemical probes for structure-function studies and as drug candidates for a number of neurological disorders and diseases. Disclosed herein is the identification of an RNA inhibitor or aptamer by an in vitro evolution approach and characterization of its mechanism of inhibition on the sites of interaction by equilibrium binding and on the receptor channel-opening rate by a laser-pulse photolysis technique. The aptamer of the invention is a noncompetitive inhibitor of AMPA-type glutamate ion channels, one that selectively inhibits the GluA2Qflip AMPA receptor subunit without any effect on other AMPA receptor subunits or on kainate or NMDA receptors. Furthermore, the aptamer preferentially inhibits the closed-channel state of GluA2Qflip with a KI=1.5 μM or by ˜15-fold over the open-channel state. The potency and selectivity of this aptamer rival those of small molecule inhibitors. Together, these properties make the aptamers of the present invention promising water-soluble, highly potent, GluA2 subunit-selective drugs.

摘要翻译： AMPA型谷氨酸离子通道的抑制剂可用作结构功能研究的生物化学探针和许多神经障碍和疾病的候选药物。 本文公开了通过体外进化方法鉴定RNA抑制剂或适体，并通过激光脉冲光解技术通过平衡结合和受体通道开放速率表征其抑制作用位点的机制。 本发明的适体是AMPA型谷氨酸离子通道的非竞争性抑制剂，其选择性地抑制GluA2Qflip AMPA受体亚基而对其它AMPA受体亚基或红藻氨酸或NMDA受体没有任何作用。 此外，适体优先抑制GluA2Qflip的闭通道状态，KI =1.5μM或比开放通道状态约15倍。 该适配体的效力和选择性与小分子抑制剂的效力和选择性相当。 这些性质一起使得本发明的适体具有潜在的水溶性，高效的GluA2亚基选择性药物。

公开(公告)号：US09200286B2

公开(公告)日：2015-12-01

申请号：US13810572

申请日：2011-07-15

申请人： Li Niu ,  Zhen Huang ,  Jae Seon Park

发明人： Li Niu ,  Zhen Huang ,  Jae Seon Park

IPC分类号： C07H21/04 ,  C12N15/115 ,  C12N15/11 ,  C12N15/113

CPC分类号： C12N15/115 ,  C12N15/111 ,  C12N15/1138 ,  C12N2310/16 ,  C12N2310/322 ,  C12N2310/3533 ,  C12N2320/13

摘要： Inhibitors of AMPA-type glutamate ion channels are useful as biochemical probes for structure-function studies and as drug candidates for a number of neurological disorders and diseases. Disclosed herein is the identification of an RNA inhibitor or aptamer by an in vitro evolution approach and characterization of its mechanism of inhibition on the sites of interaction by equilibrium binding and on the receptor channel-opening rate by a laser-pulse photolysis technique. The aptamer of the invention is a noncompetitive inhibitor of AMPA-type glutamate ion channels, one that selectively inhibits the GluA2Qflip AMPA receptor subunit without any effect on other AMPA receptor subunits or on kainate or NMDA receptors. Furthermore, the aptamer preferentially inhibits the closed-channel state of GluA2Qflip with a KI=1.5 μM or by ˜15-fold over the open-channel state. The potency and selectivity of this aptamer rival those of small molecule inhibitors. Together, these properties make the aptamers of the present invention promising water-soluble, highly potent, GluA2 subunit-selective drugs.

摘要翻译： AMPA型谷氨酸离子通道的抑制剂可用作结构功能研究的生物化学探针和许多神经障碍和疾病的候选药物。 本文公开了通过体外进化方法鉴定RNA抑制剂或适体，并通过激光脉冲光解技术通过平衡结合和受体通道开放速率表征其抑制作用位点的机制。 本发明的适体是AMPA型谷氨酸离子通道的非竞争性抑制剂，其选择性地抑制GluA2Qflip AMPA受体亚基而对其它AMPA受体亚基或红藻氨酸或NMDA受体没有任何作用。 此外，适体优先抑制GluA2Qflip的闭通道状态，KI =1.5μM或比开放通道状态约〜15倍。 该适配体的效力和选择性与小分子抑制剂的效力和选择性相当。 这些性质一起使得本发明的适体具有潜在的水溶性，高效的GluA2亚基选择性药物。