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1. 发明申请

WO1997040809A2 METHOD OF ENHANCING EFFECT OF NEUROTROPHIN WITH ANALOGUES OF p75NTR367-379 审中-公开
标题翻译：增强神经营养因子与p75 367-379类似物的作用的方法
公开(公告)号：WO1997040809A2
公开(公告)日：1997-11-06
申请号：PCT/CA1997000271
申请日：1997-04-23
申请人： QUEEN'S UNIVERSITY AT KINGSTON , RIOPELLE, Richard, J. , WEAVER, Donald, F. , ROSS, Gregory, M. , SHAMOVSKY, Igor, L.
发明人： QUEEN'S UNIVERSITY AT KINGSTON
IPC分类号： A61K00/00
CPC分类号： C07K14/70578 , A61K38/00
摘要： The present invention provides methods and compositions for enhancing an effect or effects of a neurotrophin, preferably, but not limited to, enhancing the growth and survival promoting properties of neurotrophins. The cytoplasmic region of the common neurotrophin receptor (p75 ) (rat, human, chick) contains a putative membrane-associating domain implicated in intracellular signalling. A peptide (R3) identical to this domain (p75 367-379) and various analogues of this peptide displayed circular dichroism spectra in aqueous and non-polar environments identical to the amphiphilic tetradecapeptide mastoparan (MP), and were internalized by PC12 rat pheochromocytoma cells. The R3 peptide enhanced neurite growth in PC12 cells, chick embryo primary sensory neurons, and fetal rat primary sensory neurons in vitro in the presence of sub-saturating concentrations of NGF. Peptide analogues of R3 not faithful to the distance and angular relationships of ionic groups, and the putative amphiphilic structure of p75 367-379, while still providing some enhancement, nevertheless displayed reduced potency to enhance NGF-mediated neurite growth. The common neurotrophin receptor p75 activates and translocates the nuclear transcription factor NFkB and displays pro-apoptotic effects similar to other members of the TNF receptor superfamily. A peptide mimic of the amphiphilic domain 367-379 of p75 that enhances TrkA mediated neurite growth by NGF, was used to affinity purify cytoplasmic proteins from PC12 cells. Isolated proteins contained a predominant species with an apparent molecular weight of 65 kDa. The affinity purified 65 kDa protein, as well as a protein of similar molecular mass from crude cell extracts, were identified by immunoblotting with antibody to NFkB. The 65 kDa species was chemically cross-linked to the radiolabeled analogue of the peptide mimic of p75 and immunoprecipitated by antibody to NFkB. These observations, taken together with the finding that a p75 -selective NGF antagonist blocked mediated neurite growth in limiting NGF conditions, support the view that p75 participates in neurite growth via a signaling pathway involving the translocation of NFkB.
摘要翻译：本发明提供了用于增强神经营养因子的作用或效果的方法和组合物，优选但不限于增强神经营养因子的生长和存活促进性质。常见的神经营养因子受体（p75 ）（大鼠，人，小鸡）的细胞质区域含有涉及细胞内信号传导的推定的膜结合域。与该结构域相同的肽（R3）（p75 367-379）和该肽的各种类似物在与两亲性十四肽mastoparan（MP）相同的水性和非极性环境中显示圆二色性光谱，并且被PC12内化大鼠嗜铬细胞瘤细胞。在亚饱和浓度的NGF的存在下，R3肽在体外增强了PC12细胞，鸡胚原代感觉神经元和胎儿大鼠初级感觉神经元中的神经突生长。不符合离子基团的距离和角度关系的R3的肽类似物，以及p75 367-379的推定的两亲结构，同时仍然提供一些增强，但是显示降低的效力以增强NGF介导的神经突生长。常见的神经营养因子受体p75 激活和转位核转录因子NFkB，并显示类似于TNF受体超家族其他成员的促凋亡作用。使用通过NGF增强TrkA介导的神经突生长的p75 的两亲结构域367-379的肽模拟物用于从PC12细胞中亲和纯化细胞质蛋白。分离的蛋白质含有表观分子量为65kDa的主要物种。通过用NFkB的抗体进行免疫印迹鉴定亲和纯化的65kDa蛋白质，以及来自粗细胞提取物的相似分子量的蛋白质。将65kDa物质与p75 的肽模拟物的放射性标记的类似物进行化学交联，并通过抗NFkB的抗体免疫沉淀。这些观察结果与P75 选择性NGF拮抗剂在限制NGF条件下阻断介导的神经突生长的发现一起支持p75 通过涉及NFkB易位的信号通路参与神经突生长的观点。

2. 发明申请

WO9740809A3 METHOD OF ENHANCING EFFECT OF NEUROTROPHIN WITH ANALOGUES OF P75367-379 审中-公开
标题翻译：增强神经营养因子与P75 367-379类似物的作用的方法
公开(公告)号：WO9740809A3
公开(公告)日：1998-03-26
申请号：PCT/CA9700271
申请日：1997-04-23
申请人： UNIV KINGSTON , RIOPELLE RICHARD J , WEAVER DONALD F , ROSS GREGORY M , SHAMOVSKY IGOR L
发明人： RIOPELLE RICHARD J , WEAVER DONALD F , ROSS GREGORY M , SHAMOVSKY IGOR L
IPC分类号： A61K38/00 , C07K14/705 , A61K
CPC分类号： C07K14/70578 , A61K38/00
摘要： The present invention provides methods and compositions for enhancing an effect or effects of a neurotrophin, preferably, but not limited to, enhancing the growth and survival promoting properties of neurotrophins. The cytoplasmic region of the common neurotrophin receptor (p75NTR) (rat, human, chick) contains a putative membrane-associating domain implicated in intracellular signalling. A peptide (R3) identical to this domain (p75NTR367-379) and various analogues of this peptide displayed circular dichroism spectra in aqueous and non-polar environments identical to the amphiphilic tetradecapeptide mastoparan (MP), and were internalized by PC12 rat pheochromocytoma cells. The R3 peptide enhanced neurite growth in PC12 cells, chick embryo primary sensory neurons, and fetal rat primary sensory neurons in vitro in the presence of sub-saturating concentrations of NGF. Peptide analogues of R3 not faithful to the distance and angular relationships of ionic groups, and the putative amphiphilic structure of p75NTR367-379, while still providing some enhancement, nevertheless displayed reduced potency to enhance NGF-mediated neurite growth. The common neurotrophin receptor p75NTR activates and translocates the nuclear transcription factor NFkB and displays pro-apoptotic effects similar to other members of the TNF receptor superfamily. A peptide mimic of the amphiphilic domain 367-379 of p75NTR that enhances TrkA mediated neurite growth by NGF, was used to affinity purify cytoplasmic proteins from PC12 cells. Isolated proteins contained a predominant species with an apparent molecular weight of 65 kDa. The affinity purified 65 kDa protein, as well as a protein of similar molecular mass from crude cell extracts, were identified by immunoblotting with antibody to NFkB. The 65 kDa species was chemically cross-linked to the radiolabeled analogue of the peptide mimic of p75NTR and immunoprecipitated by antibody to NFkB. These observations, taken together with the finding that a p75NTR-selective NGF antagonist blocked mediated neurite growth in limiting NGF conditions, support the view that p75NTR participates in neurite growth via a signaling pathway involving the translocation of NFkB.

3. 发明申请

WO9806048A3 Molecular modelling of neurotrophin-receptor binding 审中-公开
标题翻译：神经营养因子受体结合的分子建模
公开(公告)号：WO9806048A3
公开(公告)日：1998-08-06
申请号：PCT/CA9700539
申请日：1997-07-31
申请人： UNIV KINGSTON , SHAMOVSKY IGOR L , ROSS GREGORY M , RIOPELLE RICHARD J , WEAVER DONALD F
发明人： SHAMOVSKY IGOR L , ROSS GREGORY M , RIOPELLE RICHARD J , WEAVER DONALD F
IPC分类号： C07K14/475 , G06F17/50 , G06F19/16 , C07K1/00 , G01N33/68
CPC分类号： G06F19/16 , C07K14/475
摘要： The present invention relates to a computational method for identifying the bioactive conformations of peptide domains, in particular, the geometries of complexes of neurotrophins and their receptors. The bioactive conformation of the Nerve Growth Factor (NGF) amino and carboxyl termini (Trk binding domain) was determined. The complex of the NGF termini splits into two distinct regions: a rigid region (residues 9-11 and 112'-118') and a flexible loop (residues 1-8). The geometry of the rigid region, which is maintained by electrostatic interaction between Glu11 and Arg118', is conserved in active molecules only. The separation of the flexible loop from the rigid region is necessary in order to eliminate an influence of the loop on the biologically active conformation of the rigid region. The present invention also relates to a method for identifying and theoretically modelling specific receptor binding sites for Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) on their receptors, TrkA and TrkB, respectively. The present invention also relates to a method for identifying and theoretically modelling a receptor binding site for neurotrophins, such as NGF, BDNF, NT-3, and NT-4/5, of the common neurotrophin receptor p75NTR.

4. 发明申请

WO1998006048A2 MOLECULAR MODELLING OF NEUROTROPHIN-RECEPTOR BINDING 审中-公开
标题翻译：神经营养受体结合的分子建模
公开(公告)号：WO1998006048A2
公开(公告)日：1998-02-12
申请号：PCT/CA1997000539
申请日：1997-07-31
申请人： QUEEN'S UNIVERSITY AT KINGSTON , SHAMOVSKY, Igor, L. , ROSS, Gregory, M. , RIOPELLE, Richard, J. , WEAVER, Donald, F.
发明人： QUEEN'S UNIVERSITY AT KINGSTON
IPC分类号： G06F17/50
CPC分类号： G06F19/16 , C07K14/475
摘要： The present invention relates to a computational method for identifying the bioactive conformations of peptide domains, in particular, the geometries of complexes of neurotrophins and their receptors. The bioactive conformation of the Nerve Growth Factor (NGF) amino and carboxyl termini (Trk binding domain) was determined. The complex of the NGF termini splits into two distinct regions: a rigid region (residues 9-11 and 112'-118') and a flexible loop (residues 1-8), the geometry of the rigid region, which is maintained by electrostatic interaction between Glu and Arg , is conserved in active molecules only. The separation of the flexible loop from the rigid region is necessary in order to eliminate an influence of the loop on the biologically active conformation of the rigid region. The present invention also relates to a method for identifying and theoretically modelling specific receptor binding sites for Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) on their receptors, TrkA and TrkB, respectively. The present invention also relates to a method for identifying and theoretically modelling a receptor binding site for neurotrophins, such as NGF, BDNF, NT-3, and NT-4/5, of the common neurotrophin receptor p75 .
摘要翻译：本发明涉及用于鉴定肽结构域的生物活性构象的计算方法，特别是神经营养因子及其受体的复合物的几何形状。确定神经生长因子（NGF）氨基和羧基末端（Trk结合结构域）的生物活性构象。 NGF末端的复合物分成两个不同的区域：刚性区域（残基9-11和112'-118'）和柔性环（残基1-8），刚性区域的几何形状由静电 Glu 11和Arg <118>之间的相互作用仅在活性分子中保守。柔性环与刚性区的分离是必要的，以消除环对刚性区的生物活性构象的影响。本发明还涉及用于分别鉴定神经生长因子（NGF）和脑衍生神经营养因子（BDNF）的特异性受体结合位点对其受体TrkA和TrkB进行理论建模的方法。本发明还涉及用于鉴定和理论模拟常见神经营养因子受体p75 的神经营养因子（如NGF，BDNF，NT-3和NT-4/5）的受体结合位点的方法。

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