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1. 发明申请

US20050260711A1 Modulating pH-sensitive binding using non-natural amino acids 审中-公开
标题翻译：使用非天然氨基酸调节pH敏感结合
公开(公告)号：US20050260711A1
公开(公告)日：2005-11-24
申请号：US11094625
申请日：2005-03-30
申请人： Deepshikha Datta , William Goddard , David Tirrell , Joyce Peng
发明人： Deepshikha Datta , William Goddard , David Tirrell , Joyce Peng
IPC分类号： C07H21/04 , C07K16/32 , C07K16/44 , C12N5/06 , C12P21/06
CPC分类号： C07K16/32
摘要： The invention provides methods, systems and reagents for regulating pH-sensitive protein interaction by incorporating non-natural amino acids into the protein (e.g. an antibody, or its functional fragment, derivative, etc.). The invention also relates to specific uses in regulating pH-sensitive binding of antibodies to tumor site, by conferring enhanced tumor-specificity/selectivity. In that embodiment, the non-natural amino acids preferably have desirable side-chain pKa's, such that at below physiological pH (e.g. about pH 6.3-6.5) the non-natural amino acid confer enhanced binding to tumor antigens in acidic environments. Such non-natural amino acids can be incorporated by any suitable means, such as by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs (e.g. the degenerate codon orthogonal system.
摘要翻译：本发明提供了通过将非天然氨基酸掺入蛋白质（例如抗体或其功能片段，衍生物等）来调节pH敏感蛋白质相互作用的方法，系统和试剂。本发明还涉及通过赋予增强的肿瘤特异性/选择性来调节抗体对肿瘤部位的pH敏感结合的具体用途。在该实施方案中，非天然氨基酸优选具有所需的侧链pKa，使得在低于生理pH（例如约pH 6.3-6.5）下，非天然氨基酸在酸性环境中赋予增强的与肿瘤抗原的结合。这样的非天然氨基酸可以通过任何合适的方式并入，例如通过利用修饰的氨酰-tRNA合成酶将非标准氨基酸装入修饰的tRNA，其与通常形成的密码子形成严格的沃森 - 克里克碱基配对与天然tRNA的摆动碱基配对（如简并密码子正交系统）。

2. 发明授权

US07139665B2 Computational method for designing enzymes for incorporation of non natural amino acids into proteins 有权
标题翻译：设计用于将非天然氨基酸掺入蛋白质的酶的计算方法
公开(公告)号：US07139665B2
公开(公告)日：2006-11-21
申请号：US10375298
申请日：2003-02-27
申请人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen L. Mayo , David Tirrell
发明人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen L. Mayo , David Tirrell
IPC分类号： G06F17/00 , G06F17/11 , G06F17/30
CPC分类号： C12N9/93 , C07K1/00 , C07K2299/00 , G06F19/16
摘要： The instant invention provides methods, reagents, and computational tools for designing non-natural substrate analogs for enzymes, especially for designing unnatural amino acid analogs for aminoacyl tRNA Synthetases (AARSs), such as the Phe tRNA Synthetase. The instant invention also provides methods to incorporate unnatural amino acid analogs, especially those with interesting functional groups, into protein products to generate proteins of modified or novel functions.
摘要翻译：本发明提供了用于设计用于酶的非天然底物类似物的方法，试剂和计算工具，特别是用于设计用于氨基tRNA合成酶（AARS）的非天然氨基酸类似物，例如Phe tRNA合成酶。本发明还提供了将非天然氨基酸类似物（特别是那些具有感兴趣的官能团的类似物）掺入蛋白质产物以产生修饰或新颖功能的蛋白质的方法。

3. 发明申请

US20060177865A1 Computational method for designing enzymes for incorporation of amino acid analogs into proteins 审中-公开
标题翻译：设计用于将氨基酸类似物掺入蛋白质的酶的计算方法
公开(公告)号：US20060177865A1
公开(公告)日：2006-08-10
申请号：US11399957
申请日：2006-04-07
申请人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen Mayo , David Tirrell
发明人： Deepshikha Datta , Pin Wang , Isaac Carrico , Stephen Mayo , David Tirrell
IPC分类号： C12Q1/68 , G06F19/00 , C12N9/22
CPC分类号： C12N9/93 , C07K1/00 , C07K2299/00 , G16B15/00
摘要： The instant invention provides methods, reagents, and computational tools for designing non-natural substrate analogs for enzymes, especially for designing unnatural amino acid analogs for aminoacyl tRNA Synthetases (AARSs), such as the Phe tRNA Synthetase. The instant invention also provides methods to incorporate unnatural amino acid analogs, especially those with interesting functional groups, into protein products to generate proteins of modified or novel functions.
摘要翻译：本发明提供了用于设计用于酶的非天然底物类似物的方法，试剂和计算工具，特别是用于设计用于氨基tRNA合成酶（AARS）的非天然氨基酸类似物，例如Phe tRNA合成酶。本发明还提供了将非天然氨基酸类似物（特别是那些具有感兴趣的官能团的类似物）掺入蛋白质产物以产生修饰或新颖功能的蛋白质的方法。

4. 发明申请

US20090035836A1 MODULATING PH-SENSITIVE BINDING USING NON-NATURAL AMINO ACIDS 审中-公开
标题翻译：使用非天然氨基酸调节敏感性结合
公开(公告)号：US20090035836A1
公开(公告)日：2009-02-05
申请号：US12147379
申请日：2008-06-26
申请人： Deepshikha Datta , William A. Goddard , David Tirrell , Joyce Yaochun Peng
发明人： Deepshikha Datta , William A. Goddard , David Tirrell , Joyce Yaochun Peng
IPC分类号： C12N7/00 , C07K2/00 , C07K16/00
CPC分类号： C07K16/32
摘要： The invention provides methods, systems and reagents for regulating pH-sensitive protein interaction by incorporating non-natural amino acids into the protein (e.g. an antibody, or its functional fragment, derivative, etc.). The invention also relates to specific uses in regulating pH-sensitive binding of antibodies to tumor site, by conferring enhanced tumor-specificity/selectivity. In that embodiment, the non-natural amino acids preferably have desirable side-chain pKa's, such that at below physiological pH (e.g. about pH 6.3-6.5) the non-natural amino acid confer enhanced binding to tumor antigens in acidic environments. Such non-natural amino acids can be incorporated by any suitable means, such as by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs (e.g. the degenerate codon orthogonal system.
摘要翻译：本发明提供了通过将非天然氨基酸掺入蛋白质（例如抗体或其功能片段，衍生物等）来调节pH敏感蛋白质相互作用的方法，系统和试剂。本发明还涉及通过赋予增强的肿瘤特异性/选择性来调节抗体对肿瘤部位的pH敏感结合的具体用途。在该实施方案中，非天然氨基酸优选具有所需的侧链pKa，使得在低于生理pH（例如约pH 6.3-6.5）下，非天然氨基酸在酸性环境中赋予增强的与肿瘤抗原的结合。这样的非天然氨基酸可以通过任何合适的方式并入，例如通过利用修饰的氨酰-tRNA合成酶将非标准氨基酸装入修饰的tRNA，其与通常形成的密码子形成严格的沃森 - 克里克碱基配对与天然tRNA的摆动碱基配对（如简并密码子正交系统）。

5. 发明授权

US08518666B2 Site-specific incorporation of amino acids into molecules 失效
公开(公告)号：US08518666B2
公开(公告)日：2013-08-27
申请号：US11682272
申请日：2007-03-05
申请人： Pin Wang , Inchan Kwon , Soojin Son , Yi Tang , David Tirrell
发明人： Pin Wang , Inchan Kwon , Soojin Son , Yi Tang , David Tirrell
IPC分类号： C12N15/67 , C07H21/00 , C07K2/00
CPC分类号： C12N9/93 , C12N15/67 , C12N15/70
摘要： The invention provides certain embodiments relating to methods and compositions for incorporating non-natural amino acids into a polypeptide or protein by utilizing a mutant or modified aminoacyl-tRNA synthetase to charge the non-natural amino acid to a the corresponding tRNA. In certain embodiments, the tRNA is also modified such that the complex forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with unmodified tRNA/aminoacyl-tRNA synthetase pairs.

6. 发明申请

US20080026422A1 OVEREXPRESSION OF AMINOACYL-tRNA SYNTHETASES FOR EFFICIENT PRODUCTION OF ENGINEERED PROTEINS CONTAINING AMINO ACID ANALOGUES 有权
公开(公告)号：US20080026422A1
公开(公告)日：2008-01-31
申请号：US11671378
申请日：2007-02-05
申请人： David Tirrell , Kristi Kiick
发明人： David Tirrell , Kristi Kiick
IPC分类号： C12P21/04 , C07K14/00 , C12N1/00 , C12N1/20 , C12N15/00 , C12N5/04 , C12N5/06
CPC分类号： C12P21/00 , C12N9/003 , C12N9/93 , C12N15/67 , C12P21/02
摘要： Methods for producing modified polypeptides containing amino acid analogues are disclosed. The invention further provides purified dihydrofolate reductase polypeptides, produced by the methods of the invention, in which the methionine residues have been replaced with homoallylglycine, homoproparglycine, norvaline, norleucine, cis-crotylglycine, trans-crotylglycine, 2-aminoheptanoic acid, 2-butynylglycine and allylglycine.

7. 发明申请

US20060216760A1 Methods for proteomic profiling using non-natural amino acids 审中-公开
标题翻译：使用非天然氨基酸进行蛋白质组学分析的方法
公开(公告)号：US20060216760A1
公开(公告)日：2006-09-28
申请号：US11314323
申请日：2005-12-21
申请人： Daniela Dieterich , David Tirrell , Erin Schuman , Aaron Link
发明人： Daniela Dieterich , David Tirrell , Erin Schuman , Aaron Link
IPC分类号： G01N33/53 , C07K1/02
CPC分类号： G01N33/6842 , C07K7/06 , G01N33/5091 , G01N33/582 , G01N33/6848
摘要： The invention provides methods, reagents and systems for incorporating non-natural amino acids into proteins, preferably in vivo, using the endogenous protein synthesis machinery of an organism. The incorporated non-natural amino acids contain reactive groups for further chemical reagents, which may serve as a “handle” to enrich the proteins or fragments thereof in a number of uses, such as proteomic analysis, imaging of diseased tissues/cells, etc.
摘要翻译：本发明提供了使用生物体的内源性蛋白质合成机制将非天然氨基酸掺入蛋白质，优选在体内的方法，试剂和系统。所合并的非天然氨基酸含有用于其它化学试剂的反应性基团，其可用作在许多用途中富集蛋白质或其片段的“处理”，例如蛋白质组学分析，病变组织/细胞成像等。

8. 发明授权

US06986902B1 Polyanionic polymers which enhance fusogenicity 失效
标题翻译：增强融合性的聚阴离子聚合物
公开(公告)号：US06986902B1
公开(公告)日：2006-01-17
申请号：US09674191
申请日：1999-04-27
申请人： Tao Chen , Yuehua He , Peter Cullis , Thomas Madden , Peter Scherrer , David Tirrell , Phalgun Joshi , Jung Soo Kim
发明人： Tao Chen , Yuehua He , Peter Cullis , Thomas Madden , Peter Scherrer , David Tirrell , Phalgun Joshi , Jung Soo Kim
IPC分类号： A61K9/127 , C08G63/48 , C08G67/02 , C08F265/08
CPC分类号： A61K9/1273 , C08F8/12 , C08F8/30 , C08F8/32 , C08F120/06 , C08F297/026
摘要： The present invention relates generally to the amphiphilic polyelectrolyte, poly(2-ethylacrylic acid) and covalently bonded lipids to generate Lipo-PEAA. These Lipo-PEAA are then used to make pH-sensitive liposomes which become unstable, permeable or fusogenic with certain pH changes. In addition, this invention generally describes methods for delivering therapeutic compounds and drugs to target cells by administering to a host the pH-sensitive liposomes of the present invention.
摘要翻译：本发明一般涉及两亲性聚电解质，聚（2-乙基丙烯酸）和共价键合的脂质以产生Lipo-PEAA。然后将这些Lipo-PEAA用于制备pH敏感的脂质体，其在某些pH变化下变得不稳定，可渗透或融合。此外，本发明总体上描述了通过向宿主施用本发明的pH敏感脂质体来将治疗化合物和药物递送至靶细胞的方法。

9. 发明申请

US20050287639A1 Methods of incorporating amino acid analogs into proteins 审中-公开
标题翻译：将氨基酸类似物掺入蛋白质的方法
公开(公告)号：US20050287639A1
公开(公告)日：2005-12-29
申请号：US11130583
申请日：2005-05-17
申请人： Inchan Kwon , David Tirrell
发明人： Inchan Kwon , David Tirrell
IPC分类号： C07H21/04 , C07K14/00 , C12N1/18 , C12N1/21 , C12N9/00 , C12N15/74 , C12P21/02 , C12P21/06
CPC分类号： C12N15/113 , C07H21/02 , C12N9/93 , C12N15/70 , C12N2310/10 , C12P21/00 , C12P21/02
摘要： The invention provides a method of incorporating nonstandard amino acids into a protein by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs.
摘要翻译：本发明提供了一种通过利用修饰的氨酰-tRNA合成酶将非标准氨基酸掺入蛋白质的方法，以将非标准氨基酸装入修饰的tRNA，其与通常形成摆动碱基的密码子形成严格的沃森 - 克里克碱基配对，与天然tRNA配对。

10. 发明授权

US06835393B2 Enhanced transport using membrane disruptive agents 有权
标题翻译：增强运输使用膜破坏剂
公开(公告)号：US06835393B2
公开(公告)日：2004-12-28
申请号：US09226044
申请日：1999-01-05
申请人： Allan S. Hoffman , Patrick Stayton , Oliver W. Press , David Tirrell , Niren Murthy , Chantal Lackey , Lawrence A. Crum , Pierre D. Mourad , Tyrone M. Porter
发明人： Allan S. Hoffman , Patrick Stayton , Oliver W. Press , David Tirrell , Niren Murthy , Chantal Lackey , Lawrence A. Crum , Pierre D. Mourad , Tyrone M. Porter
IPC分类号： A61K9127
CPC分类号： A61K47/481 , A61K41/0028 , A61K41/0047 , A61K47/48376 , A61K47/6801
摘要： Compositions and methods for transport or release of therapeutic and diagnostic agents or metabolites or other analytes from cells, compartments within cells, or through cell layers or barriers are described. The compositions include a membrane barrier transport enhancing agent and are usually administered in combination with an enhancer and/or exposure to stimuli to effect disruption or altered permeability, transport or release. In a preferred embodiment, the compositions include compounds which disrupt endosomal membranes in response to the low pH in the endosomes but which are relatively inactive toward cell membranes, coupled directly or indirectly to a therapeutic or diagnostic agent. Other disruptive agents can also be used, responsive to stimuli and/or enhancers other than pH, such as light, electrical stimuli, electromagnetic stimuli, ultrasound, temperature, or combinations thereof. The compounds can be coupled by ionic, covalent or H bonds to an agent to be delivered or to a ligand which forms a complex with the agent to be delivered. Agents to be delivered can be therapeutic and/or diagnostic agents. Treatments which enhance delivery such as ultrasound, iontopheresis, and/or electrophereis can also be used with the disrupting agents.
摘要翻译：描述了用于从细胞，细胞内的细胞室或通过细胞层或屏障转运或释放治疗和诊断试剂或代谢物或其它分析物的组合物和方法。组合物包括膜屏障转运增强剂，并且通常与增强剂和/或暴露于刺激物一起施用以实现破坏或改变渗透性，运输或释放。在优选的实施方案中，组合物包括响应于内体中的低pH而破坏内体膜的化合物，但是与细胞膜相对无活性的化合物，直接或间接地与治疗剂或诊断剂偶联。还可以使用其它破坏剂，对除了pH之外的刺激和/或增强剂如光，电刺激，电磁刺激，超声，温度或其组合都有反应。这些化合物可以通过离子，共价键或H键连接到待递送的试剂上，或者与配制剂形成配合物。待递送的药剂可以是治疗和/或诊断剂。增强递送的治疗如超声波，离子分离和/或电泳也可与破坏剂一起使用。

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