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1. 发明申请

WO2008055145A3 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常CYTOPROTECTIVE活性的活化蛋白C变体，但降低抗血小板活性
公开(公告)号：WO2008055145A3
公开(公告)日：2009-04-09
申请号：PCT/US2007082980
申请日：2007-10-30
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A61K38/17 , A61K38/36 , C12N9/50
CPC分类号： A61K38/4866 , C12N9/6464 , C12Y304/21069
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其具有显着降低抗凝活性，但保持正常水平的抗凋亡活性。这些重组APC突变体的三个实例是KKK191-193AAA-APC，RR229 / 230AA-APC和RR229 / 230AA加上KKK191-193AAA-APC。本发明的APC变体和前药具有细胞保护性（抗凋亡作用）的期望性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前药来治疗受益于APC的细胞保护活性而不受APC抗凝活性影响的受试者的方法。这些受试者包括至少部分地通过细胞凋亡而导致各种器官的血管损伤或组织损伤风险的患者。在危险中，患者包括例如患有（严重）败血症，缺血/再灌注损伤，缺血性卒中，急性心肌梗死，急性或慢性神经变性疾病或经历器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

2. 发明申请

WO2008055145A9 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常CYTOPROTECTIVE活性的活化蛋白C变体，但降低抗血小板活性
公开(公告)号：WO2008055145A9
公开(公告)日：2008-07-31
申请号：PCT/US2007082980
申请日：2007-10-30
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A01N1/02 , A61K38/36 , A61K38/54
CPC分类号： A61K38/4866 , C12N9/6464 , C12Y304/21069
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其具有显着降低抗凝活性，但保持正常水平的抗凋亡活性。这些重组APC突变体的三个实例是KKK191-193AAA-APC，RR229 / 230AA-APC和RR229 / 230AA加上KKK191-193AAA-APC。本发明的APC变体和前药具有细胞保护性（抗凋亡作用）的期望性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前药来治疗受益于APC的细胞保护活性而不受APC抗凝活性影响的受试者的方法。这些受试者包括至少部分地通过细胞凋亡导致各种器官的血管损伤或组织损伤的患者。在危险中，患者包括例如患有（严重）败血症，缺血/再灌注损伤，缺血性卒中，急性心肌梗死，急性或慢性神经变性疾病或经历器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

3. 发明申请

WO2005007820A3 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常细胞保护活性但活性降低的抗凝活性的活化蛋白C变体
公开(公告)号：WO2005007820A3
公开(公告)日：2005-09-29
申请号：PCT/US2004021797
申请日：2004-07-08
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A01N1/02 , A61K38/36 , C12N20060101 , C12N9/64 , C12P21/02
CPC分类号： C12Y304/21069 , A61K38/4866 , C12N9/6464
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Two examples of such recombinant APC mutants are 3K3A-APC and 229/230-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供了重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其抗凝血活性显着降低但保留了正常水平的抗凋亡活性。这种重组APC突变体的两个例子是3K3A-APC和229/230-APC。本发明的APC变体和前药具有期望的细胞保护性（抗细胞凋亡效应）性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前体药物来治疗将受益于独立于APC的抗凝血活性的APC的细胞保护活性的受试者的方法。这些受试者包括处于各种器官中的血管或组织损伤风险的患者，至少部分由细胞凋亡引起。有风险的患者包括例如患有（严重）败血症，局部缺血/再灌注损伤，缺血性中风，急性心肌梗塞，急性或慢性神经退行性疾病或正在进行器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

4. 发明申请

WO2013070256A2 PROTEASE ACTIVATED RECEPTOR-1 (PAR1) DERIVED CYTOPROTECTIVE POLYPEPTIDES AND RELATED METHODS 审中-公开
标题翻译：蛋白酶活化的受体-1（PAR1）衍生的细胞增殖性多肽及相关方法
公开(公告)号：WO2013070256A2
公开(公告)日：2013-05-16
申请号：PCT/US2012000546
申请日：2012-11-07
申请人： SCRIPPS RESEARCH INST , MOSNIER LAURENT O , GRIFFIN JOHN H
发明人： MOSNIER LAURENT O , GRIFFIN JOHN H
CPC分类号： C07K14/705 , A61K38/00 , A61K38/177
摘要： The present invention provides novel PAR 1derived cytoprotective oligopeptides or polypeptides which typically contain at least the first 4 N-terminal residues that are substantially identical to the corresponding N-terminal residues of Met1 -Arg46 deleted human PAR 1 sequence. These cytoprotective oligopeptides or polypeptides are capable of activating PAR 1 and promoting PAR 1 cytoprotective signaling activities. The invention also provides engineered cells or transgenic non-human animals which harbor in their genome an altered PAR 1 gene that is resistant to cleavage at Arg41 and/or Arg46 residues. Additionally provided in the invention are methods of screening candidate compounds to identity additional cytoprotective compounds or cytoprotective proteases. The invention further provides therapeutic use or methods of employing a PAR 1 derived cytoprotective oligopeptide or polypeptide to treat conditions associated with tissue injuries or undesired apoptosis.
摘要翻译：本发明提供了新的PAR1衍生的细胞保护性寡肽或多肽，其通常至少含有与Met1-Arg46缺失的人PAR1序列的相应N端残基基本相同的前4个N端残基。这些细胞保护性寡肽或多肽能够激活PAR1并促进PAR1细胞保护性信号传导活性。本发明还提供了工程改造的细胞或转基因非人动物，它们在其基因组中具有对Arg41和/或Arg46残基处的切割有抗性的改变的PAR1基因。本发明另外提供了筛选候选化合物以鉴定另外的细胞保护性化合物或细胞保护性蛋白酶的方法。本发明还提供了治疗用途或使用PAR1衍生的细胞保护性寡肽或多肽来治疗与组织损伤或不希望的细胞凋亡相关的病症的方法。

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