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    Inhibitors of Memapsin 2 and use thereof
    1.
    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。

    BAL C-tail drug delivery molecules
    2.
    发明授权
    BAL C-tail drug delivery molecules 失效
    BAL C尾药物递送分子

    公开(公告)号：US5821226A

    公开(公告)日：1998-10-13

    申请号：US482262

    申请日：1995-06-07

    申请人： Jordan J. N. Tang ,  Chi-Sun Wang

    发明人： Jordan J. N. Tang ,  Chi-Sun Wang

    IPC分类号： A61K38/00 ,  A61K51/04 ,  C12N9/20 ,  A61K38/16 ,  A61K38/08 ,  A61K38/10

    CPC分类号： C12N9/20 ,  A61K51/0493 ,  A61K38/00

    摘要： Drug delivery conjugates of including a BAL C-tail peptide including all or a portion of the carboxy terminal region of human bile salt-activated lipase (BAL) conjugated to a biologically active substance are described. The C-tail peptide-drug conjugates, when orally ingested, compete with native BAL in binding to the intestinal surface, and, as a result, permit drug compositions to be delivered specifically to the intestine. Useful C-tail peptides are derivatives of the carboxy terminal region of BAL derived from all or portion of the region containing amino acid residues 539 to 722, and have a mucin-like structure containing at least three of the repeating proline-rich units of eleven amino acid residues each.

    摘要翻译： 描述了包含与生物活性物质缀合的人胆汁盐活化脂肪酶（BAL）的全部或部分羧基末端区域的BAL C尾肽的药物递送缀合物。 当口服摄取时，C尾肽 - 药物偶联物与天然BAL竞争结合肠表面，结果允许药物组合物被特异性递送至肠道。 有用的C尾肽是衍生自含有氨基酸残基539至722的全部或部分区域的BAL的羧基末端区的衍生物，并且具有包含至少三个重复的富含脯氨酸的单元的粘蛋白样结构 氨基酸残基各自。

    Method and compositions for reducing cholesterol absorption
    3.
    发明授权
    Method and compositions for reducing cholesterol absorption 失效
    减少胆固醇吸收的方法和组合物

    公开(公告)号：US5681819A

    公开(公告)日：1997-10-28

    申请号：US479160

    申请日：1995-06-07

    申请人： Jordan J. N. Tang ,  Chi-Sun Wang

    发明人： Jordan J. N. Tang ,  Chi-Sun Wang

    IPC分类号： A61K38/00 ,  A61K51/04 ,  C12N9/20 ,  A61K38/08 ,  A61K38/10 ,  A61K38/16

    CPC分类号： C12N9/20 ,  A61K51/0493 ,  A61K38/00

    摘要： Compositions derived from all or a portion of the carboxy terminal region of human bile salt-activated lipase (BAL) are described, which, when orally ingested, compete with native BAL in binding to the intestinal surface, thus reducing the physiological role of BAL in mediating the transfer of cholesterol into the intestinal cells, and, as a result, reducing the amount of cholesterol absorbed from the intestine into the blood stream. Useful derivatives of the carboxy terminal region of BAL are derived from all or portion of the region containing amino acid residues 539 to 722, and have a mucin-like structure containing at least three of the repeating proline-rich units of eleven amino acid residues each.

    摘要翻译： 描述了衍生自人胆汁盐活化脂肪酶（BAL）的羧基末端区域的全部或部分的组合物，其在口服摄取时与天然BAL竞争结合肠表面，从而降低BAL在生理学上的作用 介导胆固醇转移到肠细胞中，结果减少从肠吸收到胆固醇的胆固醇的量。 BAL的羧基末端区域的有用的衍生物衍生自含有氨基酸残基539至722的所有或部分区域，并且具有含有至少三个重复的富含脯氨酸的单元的粘蛋白样结构，每个氨基酸残基为11个氨基酸残基 。

    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。

    Catalytically active recombinant memapsin and methods of use thereof
    7.
    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。

    Catalytically active recombinant memapsin and methods of use thereof
    10.
    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：US06545127B1

    公开(公告)日：2003-04-08

    申请号：US09604608

    申请日：2000-06-27

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

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

    IPC分类号： G01N3348

    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 1.6×10−9M 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 -9 M，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。