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    Synthesis of proteins by native chemical ligation
    1.
    发明授权
    Synthesis of proteins by native chemical ligation 有权
    通过天然化学结合合成蛋白质

    公开(公告)号：US07408026B1

    公开(公告)日：2008-08-05

    申请号：US09710633

    申请日：2000-11-08

    申请人： Stephen B. H. Kent ,  Tom W. Muir ,  Philip E. Dawson

    发明人： Stephen B. H. Kent ,  Tom W. Muir ,  Philip E. Dawson

    IPC分类号： C07K1/02 ,  C07K1/107 ,  C07K14/435 ,  C07K14/52

    CPC分类号： C07K1/04 ,  C07K1/026

    摘要： Proteins of moderate size having native peptide backbones are produced by a method of native chemical ligation. Native chemical ligation employs a chemoselective reaction of two unprotected peptide segments to produce a transient thioester-linked intermediate. The transient thioester-linked intermediate then spontaneously undergoes a rearrangement to provide the full length ligation product having a native peptide bond at the ligation site. Full length ligation products are chemically identical to proteins produced by cell free synthesis. Full length ligation products may be refolded and/or oxidized, as allowed, to form native disulfide-containing protein molecules. The technique of native chemical ligation is employable for chemically synthesizing full length proteins.

    摘要翻译： 通过天然化学连接的方法产生具有天然肽骨架的中等体积的蛋白质。 天然化学连接采用两个未保护肽段的化学选择性反应产生瞬时硫酯连接的中间体。 然后瞬时硫酯连接的中间体自发地进行重排，以在连接位点提供具有天然肽键的全长连接产物。 全长连接产物与通过无细胞合成产生的蛋白质化学相同。 如所允许的，全长连接产物可以重折叠和/或氧化以形成天然二硫化物的蛋白质分子。 天然化学连接的技术可用于化学合成全长蛋白质。

    Process for characterizing proteins
    3.
    发明授权
    Process for characterizing proteins 失效
    表征蛋白质的方法

    公开(公告)号：US06495314B1

    公开(公告)日：2002-12-17

    申请号：US09043877

    申请日：1998-06-19

    申请人： Stephen B. H. Kent ,  Tom W. Muir ,  Philip E. Dawson ,  Michael C. Fitzgerald

    发明人： Stephen B. H. Kent ,  Tom W. Muir ,  Philip E. Dawson ,  Michael C. Fitzgerald

    IPC分类号： C07K104

    CPC分类号： C07K1/047

    摘要： A protein signature analysis is obtained using a peptide ladder library. The molecular signature of a protein is defined to be that subsequence of amino acid positions within the protein which are essential for the protein to bind to a target molecule. The molecular signature may be determined by screening a peptide ladder library which corresponds to the protein against the target molecule. The peptide ladder library is a library of m peptides wherein each peptide has an amino acid sequence of length m corresponding to an amino acid sequence of the protein, with one exception, viz. peptidem has a substitute amino acid at positionm and the substitute amino acid is attached by a labile bond to its neighboring amino acid. Screening the peptide ladder library against the target molecule results in a division of the original mixture into a positive (functional) pool and a negative (non-functional) pool. The pools are separated and subjected to cleavage to obtain cleavage products. Analysis of cleavage products by mass spectrometry identifies the positions that are essential for the protein to bind to its molecular target.

    摘要翻译： 使用肽梯图文件获得蛋白质特征分析。 蛋白质的分子标记被定义为蛋白质内蛋白质与靶分子结合所必需的氨基酸位置的亚序列。 可以通过筛选与靶分子相对应的蛋白质的肽梯形文库来确定分子特征。 肽梯形文库是m肽的文库，其中每个肽具有对应于蛋白质的氨基酸序列的长度m的氨基酸序列，除了一个例外， 肽在位置具有替代氨基酸，替代氨基酸通过不稳定键连接到其相邻的氨基酸。 针对靶分子筛选肽梯形图文库导致原始混合物分为正（功能）池和阴性（非功能）池。 将池分离并进行裂解以获得裂解产物。 通过质谱分析裂解产物鉴定了蛋白质与其分子靶标结合所必需的位置。

    Lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides
    5.
    发明授权
    Lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides 有权
    脂质基质辅助化学连接和膜多肽的合成

    公开(公告)号：US06451543B1

    公开(公告)日：2002-09-17

    申请号：US09384302

    申请日：1999-08-26

    申请人： Gerd. G. Kochendoerfer ,  Christie L. Hunter ,  Stephen B. H. Kent ,  Paolo Botti

    发明人： Gerd. G. Kochendoerfer ,  Christie L. Hunter ,  Stephen B. H. Kent ,  Paolo Botti

    IPC分类号： G01N3353

    CPC分类号： A61K49/0056 ,  A61K49/0041 ,  C07C229/16 ,  C07K1/023 ,  C07K1/026 ,  C07K1/04 ,  C07K1/042 ,  C07K1/045 ,  C07K14/005 ,  C07K14/215 ,  C07K14/36 ,  C07K14/43522 ,  C07K14/5421 ,  C07K14/705 ,  C07K2319/00 ,  C12N2740/16322 ,  C12N2760/16022 ,  Y10S435/87

    摘要： The present invention relates to methods and compositions for lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides that are incorporated in a lipid matrix. The invention is exemplified in production of a prefolded membrane polypeptide embedded within a lipid matrix via stepwise chemoselective chemical ligation of unprotected peptide segments, where at least one peptide segment is embedded in a lipid matrix. Any chemoselective reaction chemistry amenable for ligation of unprotected peptide segments can be employed. Suitable lipid matrices include liposomes, micelles, cell membrane patches and optically isotropic cubic lipidic phase matrices. Prefolded synthetic and semi-synthetic membrane polypeptides synthesized according to the methods and compositions of the invention also permit site-specific incorporation of one or more detectable moieties, such as a chromophore, which can be conveniently introduced during synthesis. The methods and compositions of the invention have multiple uses. For example, they can be used to assay ligand binding to membrane polypeptides and domains comprising a receptor, and thus are extremely useful for structure/function studies, drug screening/selection/design, and diagnostics and the like, including high-throughput applications. The methods and compositions of the invention are particularly suited for FRET analyses of previously inaccessible membrane polypeptides.

    摘要翻译： 本发明涉及掺入脂质基质中的脂质基质辅助化学连接和膜多肽的合成的方法和组合物。 本发明通过逐步化学选择性化学连接未受保护的肽段（其中至少一个肽片段嵌入脂质基质）生产嵌入脂质基质内的预折叠膜多肽。 可以使用适用于未保护肽段连接的任何化学选择性反应化学物质。 合适的脂质基质包括脂质体，胶束，细胞膜片和光学各向同性立体脂质相基质。 根据本发明的方法和组合物合成的预先折叠的合成和半合成膜多肽还允许位点特异性引入一个或多个可检测部分，例如发色团，其可以在合成期间方便地引入。 本发明的方法和组合物具有多种用途。 例如，它们可用于测定配体结合膜多肽和包含受体的结构域，因此对于结构/功能研究，药物筛选/选择/设计和诊断等（包括高通量应用）非常有用。 本发明的方法和组合物特别适用于以前不可接近的膜多肽的FRET分析。

    Solid phase native chemical ligation of unprotected or n-terminal cysteine protected peptides in aqueous solution
    6.
    发明授权
    Solid phase native chemical ligation of unprotected or n-terminal cysteine protected peptides in aqueous solution 失效
    在水溶液中固相化学连接未保护或N-末端半胱氨酸保护的肽

    公开(公告)号：US06326468B1

    公开(公告)日：2001-12-04

    申请号：US09097094

    申请日：1998-06-12

    申请人： Lynne Canne ,  Stephen B. H. Kent ,  Reyna Simon

    发明人： Lynne Canne ,  Stephen B. H. Kent ,  Reyna Simon

    IPC分类号： C07K102

    CPC分类号： C07K1/086 ,  C07K1/023 ,  C07K1/026 ,  C07K1/04 ,  C07K1/047

    摘要： The present invention provides methods, apparatus and kits for synthesizing assembled peptides and proteins on a solid phase with sequential ligation of three or more unprotected peptide segments using chemoselective and mild ligation chemistries in aqueous solution. Also provided are methods of monitoring solid phase sequential ligation reactions using MALDI or electrospray ionization mass spectrometry of reaction products.

    摘要翻译： 本发明提供用于在固相上合成组装的肽和蛋白质的方法，装置和试剂盒，其中使用化学选择性和温和连接化学物质在水溶液中连续连接三个或更多个未保护的肽片段。 还提供了使用MALDI或反应产物的电喷雾离子化质谱法监测固相顺序连接反应的方法。

    Pre-S gene coded peptide hepatitis B immunogens and synthetic lipid vesicle carriers
    8.
    发明授权
    Pre-S gene coded peptide hepatitis B immunogens and synthetic lipid vesicle carriers 失效
    前S基因编码肽乙型肝炎免疫原和合成脂质囊泡载体

    公开(公告)号：US5565548A

    公开(公告)日：1996-10-15

    申请号：US31735

    申请日：1993-03-15

    申请人： Alexander R. Neurath ,  Stephen B. H. Kent

    发明人： Alexander R. Neurath ,  Stephen B. H. Kent

    IPC分类号： A61K9/127 ,  A61K39/00 ,  A61K47/48 ,  C07K14/02 ,  C07K16/08 ,  G01N33/576 ,  A61K38/00 ,  A61K45/00 ,  C17K5/00

    CPC分类号： C07K14/005 ,  A61K47/48176 ,  A61K47/48315 ,  A61K47/48815 ,  A61K47/48876 ,  A61K9/1271 ,  C07K16/082 ,  G01N33/5764 ,  A61K39/00 ,  C12N2730/10122 ,  Y10S530/81

    摘要： A hepatitis B vaccine containing a peptide with an amino acid chain of at least six consecutive amino acids within the pre-S gene coded region of the envelope of hepatitis B virus. The vaccine being free of an amino acid sequence corresponding to the naturally occurring envelope proteins of hepatitis B virus and a physiologically acceptable diluent. The peptide being free or linked to a carrier. The carrier being a conventional carrier or a novel carrier including a lipid vesicle stabilized by cross-linking and having covalently bonded active sites on the outer surface thereon. Such novel carrier being useful not only to link the novel peptide containing an amino acid chain with amino acids within the pre-S gene coded region of the surface antigen of hepatitis B virus, but can also be used to bind synthetic peptide analogues of other viral proteins, as well as bacterial, allergen and parasitic proteins of man and animals. The peptides of the invention can be utilized in diagnostics for the detection of antigens and antibodies.

    摘要翻译： 一种乙型肝炎疫苗，其含有乙型肝炎病毒包膜前S基因编码区内具有至少六个连续氨基酸的氨基酸链的肽。 该疫苗不含对应于乙型肝炎病毒的天然存在的包膜蛋白的氨基酸序列和生理上可接受的稀释剂。 肽与载体无关或连接。 载体是常规载体或包含通过交联稳定并在其外表面上具有共价键合的活性位点的脂质囊泡的新型载体。 这种新型载体不仅可用于将含有氨基酸链的新肽与乙型肝炎病毒表面抗原前S基因编码区内的氨基酸连接，还可用于结合其他病毒的合成肽类似物 蛋白质，以及人和动物的细菌，变应原和寄生蛋白。 本发明的肽可用于诊断抗原和抗体的检测。

    Pre-S gene coded peptide hepatitis B immunogens, vaccines, diagnostics, and synthetic lipid vesicle carriers
    9.
    发明授权
    Pre-S gene coded peptide hepatitis B immunogens, vaccines, diagnostics, and synthetic lipid vesicle carriers 失效
    前S基因编码肽乙型肝炎免疫原，疫苗，诊断和合成脂质囊泡载体

    公开(公告)号：US5158769A

    公开(公告)日：1992-10-27

    申请号：US337784

    申请日：1989-04-13

    申请人： Alexander R. Neurath ,  Stephen B. H. Kent

    发明人： Alexander R. Neurath ,  Stephen B. H. Kent

    IPC分类号： A61K9/127 ,  A61K39/00 ,  A61K47/48 ,  C07K14/02 ,  C07K16/08 ,  G01N33/576

    CPC分类号： C07K14/005 ,  A61K47/48176 ,  A61K47/48315 ,  A61K47/48815 ,  A61K9/1271 ,  B82Y5/00 ,  C07K16/082 ,  G01N33/5761 ,  G01N33/5764 ,  A61K39/00 ,  C12N2730/10122

    摘要： A hepatitis B vaccine containing a peptide with an amino acid chain of at least six consecutive amino acids within the pre-S gene coded region of the envelope of hepatitis B virus. The vaccine being free of an amino acid sequence corresponding to the naturally occurring envelope proteins of hepatitis B virus and a physiologically acceptable diluent. The peptide being free or linked to a carrier. The carrier being a conventional carrier or a novel carrier including a lipid vesicle stabilized by cross-linking and having covalently bonded active sites on the outer surface thereon. Such novel carrier being useful not only to link the novel peptide containing an amino acid chain with amino acids within the pre-S gene coded region of the surface antigen of hepatitis B virus, but can also be used to bind synthetic peptide analogues of other viral proteins, as well as bacterial, allergen and parasitic proteins of man and animals. The peptides of the invention can be utilized in diagnostics for the detection of antigens and antibodies.

    摘要翻译： 一种乙型肝炎疫苗，其含有乙型肝炎病毒包膜前S基因编码区内具有至少六个连续氨基酸的氨基酸链的肽。 该疫苗不含对应于乙型肝炎病毒的天然存在的包膜蛋白的氨基酸序列和生理上可接受的稀释剂。 肽与载体无关或连接。 载体是常规载体或包含通过交联稳定并在其外表面上具有共价键合的活性位点的脂质囊泡的新型载体。 这种新型载体不仅可用于将含有氨基酸链的新肽与乙型肝炎病毒表面抗原前S基因编码区内的氨基酸连接，还可用于结合其他病毒的合成肽类似物 蛋白质，以及人和动物的细菌，变应原和寄生蛋白。 本发明的肽可用于诊断抗原和抗体的检测。