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    Catalytically active recombinant memapsin and methods of use thereof
    1.
    发明申请
    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：US20080112946A1

    公开(公告)日：2008-05-15

    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： A61K38/46 ,  C12N9/52 ,  C12P21/04

    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的抑制常数相对于重组前体蛋白2是1.6×10 -9 M。使用与该抑制剂的膜蛋白2键的结晶学来确定蛋白质的三维结构，以及 各种残留物在结合中的重要性。 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。

    Catalytically active recombinant memapsin and methods of use thereof
    2.
    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。

    Inhibitors of memapsin 2 and use thereof
    4.
    发明授权
    Inhibitors of memapsin 2 and use thereof 失效
    隐体蛋白2抑制剂及其用途

    公开(公告)号：US07244708B2

    公开(公告)日：2007-07-17

    申请号：US10820953

    申请日：2004-04-08

    申请人： Jordan J. N. Tang ,  Arun K. Ghosh

    发明人： Jordan J. N. Tang ,  Arun K. Ghosh

    IPC分类号： A61K38/00 ,  C07K17/00 ,  C12P21/06 ,  C12N15/09

    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 and were used to design substrate analogs of the natural -2 substrate that can inhibit the function of 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. The inhibition constant of OM99-2 is 1.6×10−9 M against recombinant pro-memapsin 2. Crystallography of memapsin 2 bound to this inhibitor was used to determine the three dimensional structure of the protein, and the importance of the various residues in binding. This information is useful for designing new inhibitors to memapsin 2, for diagnosing and treating and/or preventing 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，并用于设计可抑制膜蛋白2功能的天然-2底物的底物类似物。用于合成两个底物类似物的方法，包括在位点处的等位基因 开发了关键氨基酸残基，合成了底物类似物OMR99-1和OM99-2。 OM99-2的抑制常数相对于重组前体蛋白2是1.6×10 -9 M。结合使用该抑制剂的胶原蛋白2的结晶学来确定蛋白质的三维结构，并且重要性 的各种残基结合。 该信息对于设计用于诊断和/或预防阿尔茨海默氏病的复发蛋白2的新抑制剂是有用的。

    Protease inhibitors that overcome drug resistance
    6.
    发明授权
    Protease inhibitors that overcome drug resistance 失效
    克服耐药性的蛋白酶抑制剂

    公开(公告)号：US06969731B1

    公开(公告)日：2005-11-29

    申请号：US09506988

    申请日：2000-02-18

    申请人： Jordan J. N. Tang ,  Arun K. Ghosh

    发明人： Jordan J. N. Tang ,  Arun K. Ghosh

    IPC分类号： A61K31/34 ,  C07D307/02 ,  C07D307/20

    CPC分类号： C07D307/20

    摘要： HIV protease inhibitors are among the most powerful drugs in suppressing HIV in human patients. However, HIV developed resistance to all protease inhibitor drugs so far marketed or used in clinical trials. HIV generates resistance by mutating its protease. The strains of HIV containing mutant proteases less vulnerable to inhibitor drug are able to replicate better and maintain the infection. No effective principle exists for the design of resistance-proof HIV protease inhibitors (HIVPr). A new inhibitor has been developed based on a new concept for designing resistance invulnerable HIVPr inhibitors. In vitro data have shown that this inhibitor is effective against many known HIVPr mutants resistant to other HIVPr inhibitor drugs. The new concept is, therefore, generally applicable for the design of other resistance invulnerable HIVPr inhibitor drugs.

    摘要翻译： 艾滋病毒蛋白酶抑制剂是人类抑制艾滋病毒最强大的药物之一。 然而，艾滋病毒对所有蛋白酶抑制剂药物迄今在市场上销售或用于临床试验中产生了抵抗力 HIV通过突变其蛋白酶产生抗性。 含有不易受抑制剂药物突变的蛋白酶的HIV菌株能够更好地复制并维持感染。 没有有效的原则设计耐药HIV蛋白酶抑制剂（HIVPr）。 已经开发出一种新的抑制剂，其基础是设计抗性不可抗拒的HIVPr抑制剂的新概念。 体外数据显示，该抑制剂对许多已知的对其它HIVPr抑制剂药物有抗性的HIVPr突变体是有效的。 因此，新概念通常适用于其他抗性不可抗拒的HIVPr抑制剂药物的设计。

    Inhibitors of Memapsin 2 and use thereof
    9.
    发明授权
    Inhibitors of Memapsin 2 and use thereof 失效
    Memapsin 2抑制剂及其用途

    公开(公告)号：US07678760B2

    公开(公告)日：2010-03-16

    申请号：US11763342

    申请日：2007-06-14

    申请人： Jordan J. N. Tang ,  Arun K. Ghosh

    发明人： Jordan J. N. Tang ,  Arun K. Ghosh

    IPC分类号： A61K38/00 ,  C07K16/00

    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 bound 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pro-memapsin2结合使用与此抑制剂结合的胶原蛋白2的结晶学，以确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。