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    SUBUNIT-SELECTIVE NUCLEIC ACID INHIBITORS OF GLUTAMATE RECEPTORS
    1.
    发明申请
    SUBUNIT-SELECTIVE NUCLEIC ACID INHIBITORS OF GLUTAMATE RECEPTORS 有权
    谷氨酸受体的亚基选择性核酸抑制剂

    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。

    Subunit-selective nucleic acid inhibitors of glutamate receptors
    2.
    发明授权
    Subunit-selective nucleic acid inhibitors of glutamate receptors 有权
    亚基选择性谷氨酸受体核酸抑制剂

    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。

    Conformation-selective nucleic acid inhibitors of AMPA glutamate receptors
    3.
    发明授权
    Conformation-selective nucleic acid inhibitors of AMPA glutamate receptors 有权
    AMPA谷氨酸受体的构象选择性核​​酸抑制剂

    公开(公告)号：US08383794B2

    公开(公告)日：2013-02-26

    申请号：US12900636

    申请日：2010-10-08

    申请人： Li Niu ,  Zhen Huang

    发明人： Li Niu ,  Zhen Huang

    IPC分类号： A61K48/00 ,  C07H21/02

    CPC分类号： C07H21/02 ,  C07H21/00 ,  C07H21/04 ,  G01N2333/70571

    摘要： The present invention relates to novel nucleic acid ligands or aptamers that demonstrate potent and selective inhibition of the open-channel conformation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors.

    摘要翻译： 本发明涉及新的核酸配体或适体，其表现出对离子型谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型的开放通道构象的有效和选择性抑制。

    Nucleic acid inhibitors of glutamate receptors
    5.
    发明授权
    Nucleic acid inhibitors of glutamate receptors 有权
    谷氨酸受体的核酸抑制剂

    公开(公告)号：US07601823B2

    公开(公告)日：2009-10-13

    申请号：US11256726

    申请日：2005-10-24

    申请人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John T. Lis

    发明人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John T. Lis

    IPC分类号： C07H21/02

    CPC分类号： C12N15/115 ,  C12N2310/16

    摘要： The present invention relates to novel nucleic acid ligands or aptamers that bind to and inhibit the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors. Also disclosed is a novel combination of technologies, i.e., SELEX and laser pulse photolysis for the selection and screening of aptamers that inhibit receptor function and are useful therefore, in the treatment of diseases associated with excessive activation of ionotropic glutamate receptors.

    摘要翻译： 本发明涉及结合并抑制离子型谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型的活化的新型核酸配体或适体。 还公开了技术的新型组合，即SELEX和激光脉冲光解用于选择和筛选抑制受体功能的适体，因此可用于治疗与离子型谷氨酸受体的过度活化相关的疾病。

    Nucleic acid inhibitors of glutamate receptors
    6.
    发明申请
    Nucleic acid inhibitors of glutamate receptors 有权

    公开(公告)号：US20060148746A1

    公开(公告)日：2006-07-06

    申请号：US11256726

    申请日：2005-10-24

    申请人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John Lis

    发明人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John Lis

    IPC分类号： A61K48/00 ,  C12Q1/68 ,  C07H21/04

    CPC分类号： C12N15/115 ,  C12N2310/16

    摘要： The present invention relates to novel nucleic acid ligands or aptamers that bind to and inhibit the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors. Also disclosed is a novel combination of technologies, i.e., SELEX and laser pulse photolysis for the selection and screening of aptamers that inhibit receptor function and are useful therefore, in the treatment of diseases associated with excessive activation of ionotropic glutamate receptors.

    Nucleic acid inhibitors of glutamate receptors
    7.
    发明授权
    Nucleic acid inhibitors of glutamate receptors 有权
    谷氨酸受体的核酸抑制剂

    公开(公告)号：US08076467B2

    公开(公告)日：2011-12-13

    申请号：US12578231

    申请日：2009-10-13

    申请人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John T. Lis

    发明人： Li Niu ,  Zhen Huang ,  Hua Shi ,  John T. Lis

    IPC分类号： C07H21/02 ,  C07H21/04 ,  C40B40/06 ,  C40B40/00 ,  C40B50/00 ,  C40B30/00 ,  A61K48/00

    CPC分类号： C12N15/115 ,  C12N2310/16

    摘要： The present invention relates to novel nucleic acid ligands or aptamers that bind to and inhibit the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors. Also disclosed is a novel combination of technologies, i.e., SELEX and laser pulse photolysis for the selection and screening of aptamers that inhibit receptor function and are useful therefore, in the treatment of diseases associated with excessive activation of ionotropic glutamate receptors.

    摘要翻译： 本发明涉及结合并抑制离子型谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型的活化的新型核酸配体或适体。 还公开了技术的新型组合，即SELEX和激光脉冲光解用于选择和筛选抑制受体功能的适体，因此可用于治疗与离子型谷氨酸受体的过度活化相关的疾病。