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    Catalytically active recombinant memapsin and methods of use thereof
    34.
    发明授权
    Catalytically active recombinant memapsin and methods of use thereof 失效
    催化活性重组膜突触蛋白及其使用方法

    公开(公告)号：US07829669B2

    公开(公告)日：2010-11-09

    申请号：US11888920

    申请日：2007-08-03

    申请人： Gerald Koelsch ,  Jordan J. N. Tang ,  Lin Hong ,  Arun K. Ghosh ,  Xinli Lin

    发明人： Gerald Koelsch ,  Jordan J. N. Tang ,  Lin Hong ,  Arun K. Ghosh ,  Xinli Lin

    IPC分类号： C07K1/00

    CPC分类号： C07K5/1021 ,  A61K38/00 ,  A61K39/00 ,  C07K1/1136 ,  C07K5/06026 ,  C07K5/06043 ,  C07K5/0806 ,  C07K2299/00 ,  C12N9/6421 ,  C12N9/6478 ,  Y02A90/26 ,  Y10S514/879

    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. The substrate and subsite specificity information was used to design substrate analogs of the natural memapsin 2 substrate that can inhibit the function of memapsin 2. 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 two substrate analogues including isosteres at the sites of the critical amino acid residues were developed and the substrate analogues, OMR99-1 and OM99-2, were synthesized. OM99-2 is based on an octapeptide Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (SEQ ID NO:28) with the Leu-Ala peptide bond substituted by a transition-state isostere hydroxyethylene group (FIG. 1). The inhibition constant of OM99-2 is 1.6×10−9 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bond to this inhibitor was used to determine the three dimensional structure of the protein, as well as the importance of the various residues in binding. This information can be used by those skilled in the art to design new inhibitors, using commercially available software programs and techniques familiar to those in organic chemistry and enzymology, to design new inhibitors to memapsin 2, 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。 已经确定了催化活性酶的底物和亚位点特异性。 底物和亚位点特异性信息用于设计可以抑制膜蛋白2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memapsin 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，该类似物不能被膜蛋白2切割。开发了两个底物类似物合成的关键氨基酸残基位点处的等位基因，底物类似物OMR99- 1和OM99-2。 OM99-2基于由过渡态等电位羟基亚乙基取代的Leu-Ala肽键的八肽Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe（SEQ ID NO：28）（图1 ）。 OM99-2的抑制常数为1.6×10-9M，与重组前胶原蛋白2相似。蛋白2的结构与该抑制剂结合使用，用于测定蛋白质的三维结构，以及各种残基的重要性 绑定。 本领域技术人员可以使用本信息来设计新的抑制剂，使用商业上可获得的有机化学和酶学方面熟悉的软件程序和技术来设计新的抑制剂2，可用于诊断和治疗和/或 预防阿尔茨海默病。

    C-3 SUBSTITUTED BICYCLOOCTANE BASED HIV PROTEASE INHIBITORS
    40.
    发明申请
    C-3 SUBSTITUTED BICYCLOOCTANE BASED HIV PROTEASE INHIBITORS 有权
    基于C-3的基于双蛋白基的HIV蛋白酶抑制剂

    公开(公告)号：US20140148508A1

    公开(公告)日：2014-05-29

    申请号：US14131849

    申请日：2012-07-11

    申请人： Arun K. Ghosh ,  Hiroaki Mitsuya ,  Bruno D. Chapsal

    发明人： Arun K. Ghosh ,  Hiroaki Mitsuya ,  Bruno D. Chapsal

    IPC分类号： C07D307/935

    CPC分类号： C07D307/935

    摘要： C3-functionalized-cyclopentanyltetrahydrofuranyl carbamates that inhibit HIV proteolytic enzymes and processes for preparing the compounds are described. Compositions comprising the disclosed compound and methods of using the compounds and/or compositions for treating patients infected with HIV are also described.

    摘要翻译： 描述了抑制HIV蛋白水解酶的C3-官能化环戊基四氢呋喃基氨基甲酸酯及其制备方法。 还描述了包含所公开的化合物的组合物和用于治疗感染HIV的患者的化合物和/或组合物的方法。