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    Nucleophile-stable thioester generating compounds, methods of production and use
    2.
    发明授权
    Nucleophile-stable thioester generating compounds, methods of production and use 失效
    亲核稳定硫酯生成化合物，生产和使用方法

    公开(公告)号：US06977292B2

    公开(公告)日：2005-12-20

    申请号：US10332454

    申请日：2001-08-30

    申请人： Paolo Botti ,  James A. Bradburne ,  Stephen B. H. Kent

    发明人： Paolo Botti ,  James A. Bradburne ,  Stephen B. H. Kent

    IPC分类号： C07D317/32 ,  C07C323/52 ,  C07C323/59 ,  C07D317/34 ,  C07D319/06 ,  C07K1/00 ,  C07K1/02 ,  C07K1/04 ,  C07K7/00

    CPC分类号： C07K1/023 ,  C07C323/52 ,  C07K1/006 ,  C07K1/026 ,  C07K1/04

    摘要： The invention is directed to nucleophile-stable thioester generating compounds comprising a carboxyester thiol. The compounds have wide applicability in organic synthesis, including the generation of peptide-, polypeptide- and other polymer-thioesters. The invention is particularly useful for generating activated-thioesters from precursors that are made under conditions in which strong nucleophiles are employed, such as peptides or polypeptides made using Fmoc SPPS, as well as multi-step ligation or conjugation schemes that require (or benefit from the use of) compatible selective approaches for directing a specific ligation or conjugation reaction of interest.

    摘要翻译： 本发明涉及包含羧基酯硫醇的产生亲核试剂的硫代酯化合物。 这些化合物在有机合成中具有广泛的应用，包括产生肽，多肽和其他聚合物 - 硫酯。 本发明特别可用于从在其中使用强亲核试剂的条件下制备的前体产生活化硫酯，例如使用Fmoc SPPS制备的肽或多肽，以及需要（或从中获益）的多步连接或缀合方案 用于引导感兴趣的特异性连接或缀合反应的相容性选择性方法。

    Lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides
    4.
    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。

    Compositions for lipid matrix-assisted chemical ligation
    5.
    发明授权
    Compositions for lipid matrix-assisted chemical ligation 失效
    用于脂质基质辅助化学连接的组合物

    公开(公告)号：US07482425B2

    公开(公告)日：2009-01-27

    申请号：US10207330

    申请日：2002-07-30

    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： A61K38/00

    CPC分类号： C07K14/005 ,  C07K1/023 ,  C07K1/026 ,  C07K1/04 ,  C07K1/042 ,  C07K14/215 ,  C07K14/245 ,  C07K14/36 ,  C07K14/43522 ,  C07K14/5421 ,  C07K14/705 ,  C07K2319/00 ,  C12N2740/16322 ,  C12N2760/16022

    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。

    Synthesis of N-substituted oligomers
    7.
    发明授权
    Synthesis of N-substituted oligomers 失效
    N-取代的低聚物的合成

    公开(公告)号：US5831005A

    公开(公告)日：1998-11-03

    申请号：US441826

    申请日：1995-05-16

    申请人： Ronald N. Zuckerman ,  Janice M. Kerr ,  Stephen B. H. Kent ,  Walter H. Moos ,  Reyna J. Simon ,  Dane A. Goff

    发明人： Ronald N. Zuckerman ,  Janice M. Kerr ,  Stephen B. H. Kent ,  Walter H. Moos ,  Reyna J. Simon ,  Dane A. Goff

    IPC分类号： A61K38/00 ,  C07B61/00 ,  C07K1/04 ,  C07K7/06 ,  C07K7/08 ,  C07K14/00 ,  C08G69/10

    CPC分类号： C40B50/14 ,  C07K1/04 ,  C07K1/047 ,  C07K14/001 ,  C07K7/06 ,  C07K7/08 ,  C08G69/10 ,  A61K38/00 ,  B01J2219/00497 ,  B01J2219/00596 ,  B01J2219/0072 ,  C07B2200/11 ,  C40B40/10

    摘要： A solid-phase method for the synthesis of N-substituted oligomers, such as poly (N-substituted glycines) (referred to herein as poly NSGs) is used to obtain oligomers, such as poly NSGs of potential therapeutic interest which poly NSGs can have a wide variety of side-chain substituents. Each N-substituted glycine monomer is assembled from two "sub-monomers" directly on the solid support. Each cycle of monomer addition consists of two steps: (1) acylation of a secondary amine bound to the support with an acylating agent comprising a leaving group capable of nucleophilic is displacement by --NH.sub.2, such as a haloacetic acid, and (2) introduction of the side-chain by nucleophilic displacement of the leaving group, such as halogen (as a resin-bound .alpha.-haloacetamide) with a sufficient amount of a second sub-monomer comprising an --NH.sub.2 group, such as a primary amine, alkoxyamine, semicarbazide, acyl hydrazide, carbazate or the like. Repetition of the two step cycle of acylation and displacement gives the desired oligomers. The efficient synthesis of a wide variety of oligomeric NSGs using automated synthesis technology of the present method makes these oligomers attractive candidates for the generation and rapid screening of diverse peptidomimetic libraries. The oligomers of the invention, such as N-substituted glycines (i.e. poly NSGs) disclosed here provide a new class of peptide-like compounds not found in nature, but which are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability.

    摘要翻译： 用于合成N-取代的低聚物（例如聚（N-取代的甘氨酸）（本文称为多聚NSG））的固相方法用于获得低聚物，例如聚NSG可具有的潜在治疗兴趣的聚NSG 各种各样的侧链取代基。 每个N-取代的甘氨酸单体直接在固体支持物上由两个“亚单体”组装。 单体添加的每个循环由两个步骤组成：（1）用包含能够亲核的离去基团的酰化剂与载体结合的仲胺的酰化被-NH 2取代，例如卤代乙酸，和（2）引入 的侧链通过亲核取代离去基团，例如卤素（作为树脂结合的α-卤代乙酰胺）与足够量的包含-NH 2基团的第二亚单体如伯胺，烷氧基胺， 氨基脲，酰肼，卡巴肼等。 重复酰化和置换的两个步骤循环，得到所需的低聚物。 使用本发明方法的自动化合成技术有效合成各种各样的低聚NSG使得这些寡聚物成为用于不同肽模拟文库的产生和快速筛选的有吸引力的候选者。 本文公开的本发明的低聚物，例如N-取代的甘氨酸（即多聚NSG）提供了一类新型的肽样化合物，它们在自然界中没有发现，但是它们是合成可及的，并且已被证明具有显着的生物活性和蛋白水解稳定性 。

    Pre-S gene coded peptide hepatitis B immunogens, vaccines, diagnostics, and synthetic lipid vesicle carriers
    8.
    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：US5204096A

    公开(公告)日：1993-04-20

    申请号：US338028

    申请日：1989-04-14

    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 ,  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 or 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。 这种新型载体不仅用于将含有氨基酸链的新肽与表面抗原或乙型肝炎病毒的S前编码区之前的氨基酸连接，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。

    Automated polypeptide synthesis process
    9.
    发明授权
    Automated polypeptide synthesis process 失效
    自动多肽合成过程

    公开(公告)号：US4816513A

    公开(公告)日：1989-03-28

    申请号：US53324

    申请日：1987-05-22

    申请人： John Bridgham ,  Timothy G. Geiser ,  Michael W. Hunkapiller ,  Stephen B. H. Kent ,  Mark P. Marriott ,  Paul O. Ramstad ,  Eric S. Nordman

    发明人： John Bridgham ,  Timothy G. Geiser ,  Michael W. Hunkapiller ,  Stephen B. H. Kent ,  Mark P. Marriott ,  Paul O. Ramstad ,  Eric S. Nordman

    IPC分类号： C07K1/00 ,  B01J19/00 ,  C07K1/04 ,  C40B40/10 ,  C40B60/14 ,  C08L89/00 ,  C07C103/52

    CPC分类号： C07K1/045 ,  B01J19/0046 ,  B01J2219/00286 ,  B01J2219/00389 ,  B01J2219/00484 ,  B01J2219/00488 ,  B01J2219/0049 ,  B01J2219/00495 ,  B01J2219/005 ,  B01J2219/0059 ,  B01J2219/00596 ,  B01J2219/00689 ,  B01J2219/00695 ,  B01J2219/00725 ,  C40B40/10 ,  C40B60/14

    摘要： An apparatus is provided for automatically constructing a polypeptide of high purity, up to 50 amino acids in length, using only single couplings. The apparatus includes an activation system for receiving protected amino acids, one kind at a time, having a common vessel (an activator vessel) in which to activate each of the amino acids. Also included is a reaction vessel for containing a resin used in solid-phase peptide synthesis for attaching a peptide chain thereto. A transfer system is also provided, which operates under control of a computer, to transfer the activated species from the activation system to the reaction vessel and to transfer amino acids, reagents, gases, and solvents from one part of the apparatus to another. The activator system also includes a temperature controlled concentrator vessel in which an activator solvent is replaced by a coupling solvent to enhance the coupling of the activated species to the peptide chain in the reaction vessel. Also included in the synthesizer system is a vortexer for affecting total washing of materials in the reaction vessel and the reaction vessel itself, an automated peptide resin sampling system, and an autodelivery system for providing individual containers of amino acid to the synthesizer in the order desired in the peptide sequence. A liquid sensor system is also included to monitor transitions between gases and liquids in specific tubes in the synthesizer in order to provide input signals to the computer system for control purposes. The computer system software which controls the operation of the synthesizer is organized according to a series of menus which allows the user of the system to select individual cycles of operation for each vessel in the synthesizer. In addition, an algorithm has been developed which provides for optimum efficiency in the production of a peptide for any given selection of cycles.

    摘要翻译： 提供了一种用于仅使用单个耦合自动构建高纯度多达50个氨基酸长度的多肽的装置。 该装置包括用于一次接收受保护的氨基酸的激活系统，其具有在其中激活每个氨基酸的共同血管（活化剂容器）。 还包括用于含有固相肽合成中用于连接肽链的树脂的反应容器。 还提供了在计算机控制下操作的转移系统，以将活化物质从活化系统转移到反应容器中，并将氨基酸，试剂，气体和溶剂从设备的一部分转移到另一部分。 活化剂体系还包括温度控制的浓缩容器，其中活化剂溶剂被偶联溶剂代替以增强活化物质与反应容器中的肽链的偶联。 还包括在合成器系统中的是用于影响反应容器和反应容器本身中的材料的全部洗涤的涡流器，自动化肽树脂取样系统和用于按合适的顺序向合成器提供单个氨基酸容器的自动输送系统 在肽序列中。 还包括液体传感器系统以监测合成器中特定管中的气体和液体之间的转换，以便为控制目的向计算机系统提供输入信号。 控制合成器操作的计算机系统软件根据一系列菜单进行组织，这些菜单允许系统的用户为合成器中的每个容器选择各个操作周期。 此外，已经开发了一种算法，其提供用于任何给定选择周期的肽的生产的最佳效率。