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1. 发明授权

US08093044B2 Methods for identifying inhibitors of botulinum neurotoxins 有权
标题翻译：鉴定肉毒杆菌神经毒素抑制剂的方法
公开(公告)号：US08093044B2
公开(公告)日：2012-01-10
申请号：US12630336
申请日：2009-12-03
申请人： Randall Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
发明人： Randall Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
IPC分类号： C07K14/00 , A61K39/08 , C12N5/10
CPC分类号： C07K14/705 , C12Q1/37 , G01N33/5014 , G01N2500/04
摘要： A system and method for identifying a botulinum neurotoxin inhibitor employing a botulinum neurotoxin substrate complex having a peptide substrate, preferably SNAP-25, a reporter domain on one side of said peptide substrate and an immobilization domain on the opposite side of said peptide substrate. The botulinum neurotoxin inhibitor is identified by its ability to decrease the relative amount of cleaved complex, detected through measuring a decrease in complex bound to a solid support. The method of the present invention also utilizes novel cells that express a botulinum neurotoxin substrate complex. The methods of the present invention are adapted for cell based screening to monitor the catalytic activity of a BoNT in living cells and to identify molecules that inhibit the catalytic activity of a BoNT in living cells. Also provided are novel stable cell lines that express the botulinum toxin substrate complex and viral vectors capable of efficiently expressing an active light chain of the BoNT within mammalian cells.
摘要翻译：一种使用具有肽底物的肉毒杆菌神经毒素底物复合物鉴定肉毒杆菌神经毒素抑制剂的系统和方法，优选SNAP-25，所述肽底物一侧的报道结构域和所述肽底物相反侧的固定结构域。肉毒杆菌神经毒素抑制剂通过其降低切割复合物的相对量的能力来鉴定，通过测量与固体支持物结合的复合物的降低来检测。本发明的方法还利用表达肉毒神经毒素底物复合物的新细胞。本发明的方法适用于基于细胞的筛选以监测活细胞中BoNT的催化活性并鉴定抑制活细胞中BoNT的催化活性的分子。还提供了表达肉毒杆菌毒素底物复合物的新型稳定细胞系和能够在哺乳动物细胞内有效表达BoNT活性轻链的病毒载体。

2. 发明申请

US20120237955A1 METHODS FOR IDENTIFYING INHIBITORS OF BOTULINUM NEUROTOXINS 审中-公开
标题翻译：用于鉴定嗜碱性粒细胞毒素抑制剂的方法
公开(公告)号：US20120237955A1
公开(公告)日：2012-09-20
申请号：US13345691
申请日：2012-01-07
申请人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
发明人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
IPC分类号： G01N21/64
CPC分类号： C07K14/705 , C12Q1/37 , G01N33/5014 , G01N2500/04
摘要： A system and method for identifying a botulinum neurotoxin inhibitor employing a botulinum neurotoxin substrate complex having a peptide substrate, preferably SNAP-25, a reporter domain on one side of said peptide substrate and an immobilization domain on the opposite side of said peptide substrate. The botulinum neurotoxin inhibitor is identified by its ability to decrease the relative amount of cleaved complex, detected through measuring a decrease in complex bound to a solid support. The method of the present invention also utilizes novel cells that express a botulinum neurotoxin substrate complex. Also provided are novel stable cell lines that express the botulinum toxin substrate complex and viral vectors capable of efficiently expressing an active light chain of the BoNT within mammalian cells.
摘要翻译：一种使用具有肽底物的肉毒杆菌神经毒素底物复合物鉴定肉毒杆菌神经毒素抑制剂的系统和方法，优选SNAP-25，所述肽底物一侧的报道结构域和所述肽底物相反侧的固定结构域。肉毒杆菌神经毒素抑制剂通过其降低切割复合物的相对量的能力来鉴定，通过测量与固体支持物结合的复合物的降低来检测。本发明的方法还利用表达肉毒神经毒素底物复合物的新细胞。还提供了表达肉毒杆菌毒素底物复合物的新型稳定细胞系和能够在哺乳动物细胞内有效表达BoNT活性轻链的病毒载体。

3. 发明申请

US20100204054A1 METHODS FOR IDENTIFYING INHIBITORS OF BOTULINUM NEUROTOXINS 有权
标题翻译：用于鉴定嗜碱性粒细胞毒素抑制剂的方法
公开(公告)号：US20100204054A1
公开(公告)日：2010-08-12
申请号：US12630336
申请日：2009-12-03
申请人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
发明人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
IPC分类号： C40B30/04 , C12N1/20 , G01N33/53
CPC分类号： C07K14/705 , C12Q1/37 , G01N33/5014 , G01N2500/04
摘要： A system and method for identifying a botulinum neurotoxin inhibitor employing a botulinum neurotoxin substrate complex having a peptide substrate, preferably SNAP-25, a reporter domain on one side of said peptide substrate and an immobilization domain on the opposite side of said peptide substrate. The botulinum neurotoxin inhibitor is identified by its ability to decrease the relative amount of cleaved complex, detected through measuring a decrease in complex bound to a solid support. The method of the present invention also utilizes novel cells that express a botulinum neurotoxin substrate complex. The methods of the present invention are adapted for cell based screening to monitor the catalytic activity of a BoNT in living cells and to identify molecules that inhibit the catalytic activity of a BoNT in living cells. Also provided are novel stable cell lines that express the botulinum toxin substrate complex and viral vectors capable of efficiently expressing an active light chain of the BoNT within mammalian cells.
摘要翻译：一种使用具有肽底物的肉毒杆菌神经毒素底物复合物鉴定肉毒杆菌神经毒素抑制剂的系统和方法，优选SNAP-25，所述肽底物一侧的报道结构域和所述肽底物相反侧的固定结构域。肉毒杆菌神经毒素抑制剂通过其降低切割复合物的相对量的能力来鉴定，通过测量与固体支持物结合的复合物的降低来检测。本发明的方法还利用表达肉毒神经毒素底物复合物的新细胞。本发明的方法适用于基于细胞的筛选以监测活细胞中BoNT的催化活性并鉴定抑制活细胞中BoNT的催化活性的分子。还提供了表达肉毒杆菌毒素底物复合物的新型稳定细胞系和能够在哺乳动物细胞内有效表达BoNT活性轻链的病毒载体。

4. 发明授权

US09005911B2 Methods for identifying inhibitors of botulinum neurotoxins 有权
标题翻译：鉴定肉毒杆菌神经毒素抑制剂的方法
公开(公告)号：US09005911B2
公开(公告)日：2015-04-14
申请号：US13345691
申请日：2012-01-07
申请人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
发明人： Randall L. Kincaid , George Oyler , Yien Che Tsai , Paul S. Fishman
IPC分类号： G01N33/53 , A61K39/08 , C07K14/705 , C12Q1/37 , G01N33/50
CPC分类号： C07K14/705 , C12Q1/37 , G01N33/5014 , G01N2500/04
摘要： A system and method for identifying a botulinum neurotoxin inhibitor employing a botulinum neurotoxin substrate complex having a peptide substrate, preferably SNAP-25, a reporter domain on one side of said peptide substrate and an immobilization domain on the opposite side of said peptide substrate. The botulinum neurotoxin inhibitor is identified by its ability to decrease the relative amount of cleaved complex, detected through measuring a decrease in complex bound to a solid support. The method of the present invention also utilizes novel cells that express a botulinum neurotoxin substrate complex. Also provided are novel stable cell lines that express the botulinum toxin substrate complex and viral vectors capable of efficiently expressing an active light chain of the BoNT within mammalian cells.
摘要翻译：一种使用具有肽底物的肉毒杆菌神经毒素底物复合物鉴定肉毒杆菌神经毒素抑制剂的系统和方法，优选SNAP-25，所述肽底物一侧的报道结构域和所述肽底物相反侧的固定结构域。肉毒杆菌神经毒素抑制剂通过其降低切割复合物的相对量的能力来鉴定，通过测量与固体支持物结合的复合物的降低来检测。本发明的方法还利用表达肉毒神经毒素底物复合物的新细胞。还提供了表达肉毒杆菌毒素底物复合物的新型稳定细胞系和能够在哺乳动物细胞内有效表达BoNT活性轻链的病毒载体。

5. 发明申请

US20110143362A1 METHOD FOR IDENTIFICATION OF PROTEASE ACTIVITY INHIBITORS AND ASSAYING THE PRESENCE OF PROTEASE ACTIVITY 审中-公开
标题翻译：鉴定蛋白酶活性抑制剂的方法和测定蛋白酶活性的存在
公开(公告)号：US20110143362A1
公开(公告)日：2011-06-16
申请号：US12962610
申请日：2010-12-07
申请人： George Oyler , Yung-Nien Chang , Yien Che Tsai
发明人： George Oyler , Yung-Nien Chang , Yien Che Tsai
IPC分类号： C12Q1/68 , C12N15/63
CPC分类号： C12Q1/37 , C12N15/1034 , C12N15/1086 , C12N15/635 , C12Q1/6897 , C12Q2522/101 , C12Q2521/537
摘要： A system for the identification of proteases and protease inhibitors is provided. The system has at least two components. The first component is a reporter construct with at least one binding site, a transcriptional promoter, an inducible promoter region, and at least one reporter gene, all functionally connected for expression of the reporter gene(s) in functional coordination with a transcriptional activation agent. The second component is a transcriptional activation agent comprising a nucleic acid binding domain, at least one protease substrate domain, and at least one transcriptional activation domain for an inducible promoter. The system allows detection and evaluation of agents affecting protease activity directed to the protease substrate domain. The system also allows for the detection of the presence of proteases in environmental samples.
摘要翻译：提供了用于鉴定蛋白酶和蛋白酶抑制剂的系统。该系统至少有两个组件。第一组分是具有至少一个结合位点，转录启动子，诱导型启动子区和至少一个报告基因的报道构建体，其全部功能连接用于与转录激活剂的功能性配位的报道基因的表达。第二组分是包含核酸结合结构域，至少一个蛋白酶底物结构域和用于诱导型启动子的至少一个转录激活结构域的转录激活剂。该系统允许检测和评估影响针对蛋白酶底物结构域的蛋白酶活性的试剂。该系统还允许检测环境样品中蛋白酶的存在。

6. 发明授权

US08343743B2 Designer ubiquitin ligases having a non-cleavable SNAP25 domain and E3-ligase domain 失效
标题翻译：具有不可切割的SNAP25结构域和E3连接酶结构域的设计者泛素连接酶
公开(公告)号：US08343743B2
公开(公告)日：2013-01-01
申请号：US12482420
申请日：2009-06-10
申请人： George A. Oyler , Yien Che Tsai
发明人： George A. Oyler , Yien Che Tsai
IPC分类号： C12N9/00 , C12N1/20 , C12N15/00 , C07H21/04 , A61K38/43
CPC分类号： C12N9/93 , A61K38/4886 , Y02A50/471
摘要： The present invention relates to a designer or recombinant ubiquitin ligase molecule that includes a toxin binding domain that is specific for a toxin active fragment, wherein the toxin active fragment is an enzymatically active fragment of one or more toxins or toxin serotypes; and an E3-ligase domain that comprises an E3-ligase or polypeptide that facilitates E2-mediated ubiquitination of the toxin active fragment. In an embodiment, the composition further includes a delivery system that allow the designer ubiquitin ligase to enter the cell. The present invention further includes methods for treating an individual intoxicated with a toxin by administering the designer ubiquitin ligase of the present invention.
摘要翻译：本发明涉及一种设计者或重组泛素连接酶分子，其包括对毒素活性片段特异的毒素结合结构域，其中所述毒素活性片段是一种或多种毒素或毒素血清型的酶活性片段; 和E3连接酶结构域，其包含促进E2介导的毒素活性片段的泛素化的E3连接酶或多肽。在一个实施方案中，组合物还包括允许设计者泛素连接酶进入细胞的递送系统。本发明还包括通过施用本发明的设计者泛素连接酶来治疗用毒素中毒的个体的方法。

7. 发明授权

US08940482B1 N-end rule protease activity indication methods and uses thereof 有权
标题翻译： N端规则蛋白酶活性指示方法及其用途
公开(公告)号：US08940482B1
公开(公告)日：2015-01-27
申请号：US13159284
申请日：2011-06-13
申请人： George A. Oyler , Yien Che Tsai
发明人： George A. Oyler , Yien Che Tsai
IPC分类号： C12Q1/37
CPC分类号： C12Q1/66 , C12Q1/37 , G01N2333/33 , G01N2333/952 , G01N2500/10
摘要： A cell based assay for detection for protease activity is disclosed. In the assay a cell is engineered to express a protease substrate with at least one label, preferably on its C-terminus. Cleavage of the substrate by the protease that recognizes it results in a C-terminal fragment and a N-terminal fragment, where the fragment having the label is subject to ubiquitin proteasome degradation. The assay measures the disappearance of the label due to degradation of the fragment to which it is attached. A cell free assay is also described for detection of protease activity. In the cell free assay, the protease substrate is expressed in a solution that includes the elements of the ubiquitin proteasome pathway for degradation of the fragment. The assay measures the disappearance of the label attached to the fragment that results from cleavage by the protease.
摘要翻译：公开了一种用于蛋白酶活性检测的基于细胞的测定法。在测定中，将细胞工程化以表达具有至少一个标记的蛋白质底物，优选在其C-末端。通过识别它的蛋白酶切割底物导致C-末端片段和N-末端片段，其中具有标记的片段经受泛素蛋白酶体降解。该测定法测量标签由于其附着的片段的降解而消失。还描述了无细胞测定法用于检测蛋白酶活性。在无细胞测定中，蛋白酶底物在包含用于降解片段的泛素蛋白酶体途径的元件的溶液中表达。该测定法测量由蛋白酶切割导致的片段附着的标记物的消失。

8. 发明申请

US20150010931A1 N-END RULE PROTEASE ACTIVITY INDICATION METHODS AND USES THEREOF 有权
标题翻译： N末端规则蛋白酶活性指示方法及其用途
公开(公告)号：US20150010931A1
公开(公告)日：2015-01-08
申请号：US13159284
申请日：2011-06-13
申请人： George A. Oyler , Yien Che Tsai
发明人： George A. Oyler , Yien Che Tsai
IPC分类号： C12Q1/66 , C12Q1/37
CPC分类号： C12Q1/66 , C12Q1/37 , G01N2333/33 , G01N2333/952 , G01N2500/10
摘要： A cell based assay for detection for protease activity is disclosed. In the assay a cell is engineered to express a protease substrate with at least one label, preferably on its C-terminus. Cleavage of the substrate by the protease that recognizes it results in a C-terminal fragment and a N-terminal fragment, where the fragment having the label is subject to ubiquitin proteasome degradation. The assay measures the disappearance of the label due to degradation of the fragment to which it is attached. A cell free assay is also described for detection of protease activity. In the cell free assay, the protease substrate is expressed in a solution that includes the elements of the ubiquitin proteasome pathway for degradation of the fragment. The assay measures the disappearance of the label attached to the fragment that results from cleavage by the protease.
摘要翻译：公开了一种用于蛋白酶活性检测的基于细胞的测定法。在测定中，将细胞工程化以表达具有至少一个标记的蛋白质底物，优选在其C-末端。通过识别它的蛋白酶切割底物导致C-末端片段和N-末端片段，其中具有标记的片段经受泛素蛋白酶体降解。该测定法测量标签由于其附着的片段的降解而消失。还描述了无细胞测定法用于检测蛋白酶活性。在无细胞测定中，蛋白酶底物在包含用于降解片段的泛素蛋白酶体途径的元件的溶液中表达。该测定法测量由蛋白酶切割导致的片段附着的标记物的消失。

9. 发明授权

US08420776B2 Ube2G2 binding domain in the ubiquitin ligase gp78 and methods of use thereof 有权
标题翻译： Uub2g2结合域在泛素连接酶gp78及其使用方法
公开(公告)号：US08420776B2
公开(公告)日：2013-04-16
申请号：US11597453
申请日：2005-04-27
申请人： Allan Weissman , Jennifer Mariano , Bo Chen , Yien Che Tsai
发明人： Allan Weissman , Jennifer Mariano , Bo Chen , Yien Che Tsai
IPC分类号： C07K14/435 , C12P21/02
CPC分类号： C12N9/93
摘要： The present invention features isolated nucleic acid molecules, designated G2BD nucleic acid molecules, which encode the binding site from the gp78 ubiquitin ligase that binds to the Ube2G2 ubiquitin conjugating enzyme. The invention further provides isolated G2BD proteins and fusion proteins. Still further provided are diagnostic and therapeutic methods, as well as screening assays utilizing compositions of the invention.
摘要翻译：本发明的特征在于分离的核酸分子，命名为G2BD核酸分子，其编码结合于Ube2G2泛素缀合酶的gp78泛素连接酶的结合位点。本发明还提供了分离的G2BD蛋白和融合蛋白。还提供了诊断和治疗方法，以及利用本发明组合物的筛选测定。

10. 发明申请

US20100015116A1 Designer Ubiquitin Ligases For Regulation Of Intracellular Pathogenic Proteins 失效
标题翻译：设计人员用于调节细胞内病原性蛋白质的泛素连接酶
公开(公告)号：US20100015116A1
公开(公告)日：2010-01-21
申请号：US12482420
申请日：2009-06-10
申请人： George A. Oyler , Yien Che Tsai
发明人： George A. Oyler , Yien Che Tsai
IPC分类号： A61K38/43 , C12N9/00 , C12N5/02
CPC分类号： C12N9/93 , A61K38/4886 , Y02A50/471
摘要： The present invention relates to a designer or recombinant ubiquitin ligase molecule that includes a toxin binding domain that is specific for a toxin active fragment, wherein the toxin active fragment is an enzymatically active fragment of one or more toxins or toxin serotypes; and an E3-ligase domain that comprises an E3-ligase or polypeptide that facilitates E2-mediated ubiquitination of the toxin active fragment. In an embodiment, the composition further includes a delivery system that allow the designer ubiquitin ligase to enter the cell. The present invention further includes methods for treating an individual intoxicated with a toxin by administering the designer ubiquitin ligase of the present invention.
摘要翻译：本发明涉及一种设计者或重组泛素连接酶分子，其包括对毒素活性片段特异的毒素结合结构域，其中所述毒素活性片段是一种或多种毒素或毒素血清型的酶活性片段; 和E3连接酶结构域，其包含促进E2介导的毒素活性片段的泛素化的E3连接酶或多肽。在一个实施方案中，组合物还包括允许设计者泛素连接酶进入细胞的递送系统。本发明还包括通过施用本发明的设计者泛素连接酶来治疗用毒素中毒的个体的方法。

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