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1. 发明申请

WO02053594A3 INHIBITORS OF MEMAPSIN 2 AND USE THEREOF 审中-公开
标题翻译： MEMAPSIN 2的抑制剂及其用途
公开(公告)号：WO02053594A3
公开(公告)日：2004-01-08
申请号：PCT/US0150826
申请日：2001-12-28
申请人： OKLAHOMA MED RES FOUND , UNIV ILLINOIS , TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
发明人： TANG JORDAN J N , KOELSCH GERALD , GHOSH ARUN K
IPC分类号： A61K38/00 , A61K45/00 , A61P25/28 , A61P43/00 , C07K5/02 , C07K14/81 , C12N9/64 , C12Q1/37 , G01N33/68 , A61K38/55 , C07K5/03
CPC分类号： C12N9/6478 , A61K38/00 , C07K5/0207 , C07K14/8142 , C07K2299/00 , C12Q1/37 , G01N33/6896
摘要： Methods for the production of purified, catalytically active, recombinant memapsin 2 have been developed. The substrate and subsite specificity of the catalytically active enzyme have been determined by a method which determines the initial hydrolysis rate of the substrate by using MALDI-TOF/MS. Alternatively, the subsite specificity of mepapsin can be determined by probing a library of inhibitors with memapsin 2 and subsequently detecting the bound memapsin 2 with an antibody raised to memapsin 2 and an alkaline phosphatase conjugated secondary antibody. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin2. The substrate analogs are based on peptide sequences, shown to be related to the natural peptide substrates for memapsin 2. The substrate analogs contain at least one analog of an amide bond which is not capable of being cleaved by memapsin 2. Processes for the synthesis of substrate analogues including isoteres at the sites of the critical amino acid residues were developed and the more than seventy substrate analogues were synthetized, among which MMI-005, MMI-012, MMI-017, MMI-018, MMI-025, MMI-026, MMI-037, MMI-039, MMI-040, MMI-066, MMI-070, and MMI-071 have inhibition constants in the range of 1.4-61.4 x 10 M against recombinant pro-memapsin 2. These inhibitors are useful in diagnostics and for the treatment and/or prevention of Alzheimer's disease.
摘要翻译：已经开发了用于生产纯化的，催化活性的重组突变蛋白2的方法。已经通过使用MALDI-TOF / MS确定底物的初始水解速率的方法确定了催化活性酶的底物和亚位点特异性。或者，可以通过用突变蛋白2探测抑制剂文库并随后用提出到膜蛋白酶2的抗体和碱性磷酸酶缀合的第二抗体检测结合的突变蛋白2来确定片段蛋白的亚位点特异性。底物和亚位点特异性信息用于设计可抑制memapsin2功能的天然memapsin 2底物的底物类似物。底物类似物基于肽序列，显示与复制蛋白2的天然肽底物相关。底物类似物含有至少一个酰胺键的类似物，其不能被膜蛋白2切割。合成方法开发了包含在关键氨基酸残基位点的同位素的底物类似物，合成了70多个底物类似物，其中MMI-005，MMI-012，MMI-017，MMI-018，MMI-025，MMI-026 MMI-037，MMI-039，MMI-040，MMI-066，MMI-070和MMI-071对重组pro-memapsin2具有在1.4-61.4×10 -9 M范围内的抑制常数。这些抑制剂可用于诊断和治疗和/或预防阿尔茨海默病。

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