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    Thin film HPMP matrix systems and methods for constructing and displaying ligands
    1.
    发明授权
    Thin film HPMP matrix systems and methods for constructing and displaying ligands 失效
    薄膜HPMP矩阵系统和构建和显示配体的方法

    公开(公告)号：US5576220A

    公开(公告)日：1996-11-19

    申请号：US19725

    申请日：1993-02-19

    申请人： Derek Hudson ,  Charles R. Johnson ,  Michael J. Ross ,  Kevin R. Shoemaker ,  Robert T. Cass ,  Lutz B. Giebel

    发明人： Derek Hudson ,  Charles R. Johnson ,  Michael J. Ross ,  Kevin R. Shoemaker ,  Robert T. Cass ,  Lutz B. Giebel

    IPC分类号： A61K47/48 ,  B01J19/00 ,  B01J20/32 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  G01N33/545 ,  G01N33/543

    CPC分类号： G01N33/545 ,  A61K47/48984 ,  B01J19/0046 ,  B01J20/3204 ,  B01J20/3208 ,  B01J20/3219 ,  B01J20/3274 ,  B01J2219/00497 ,  B01J2219/00536 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/00619 ,  B01J2219/00626 ,  B01J2219/00637 ,  B01J2219/00639 ,  B01J2219/00641 ,  B01J2219/00664 ,  B01J2219/0072 ,  B01J2219/00722 ,  B01J2219/00725 ,  B01J2219/00731 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  Y10S436/807

    摘要： The invention relates to methods and systems of unhindered construction and display of tethered organic ligand molecules, and more particularly to preparation and use of thin film, substantially non-crosslinked hydrophilic polar multi-functionalized polymers (HPMPs) anchored to a variety of functionalized substrates so that the HPMP forms a thin film matrix layer providing a unique highly hydrated, high dielectric environment equivalent to an aqueous solution, for affinity binding of Ligands (L) to Tagged Target Molecules (TTMs). Ligands, and especially MER.sub.n ligand libraries such as peptide libraries, are singly tethered to the HPMP by a "permanent" strong covalent bond so that subsequent displacement of the TTM does not also displace the ligand from the HPMP, thereby making the HPMP tethered Ligand library reusable. The HPMP thin film is on the order of 200-2000 .ANG. thick, is highly accessible (to the TTMs), and permits flexible, 3-D display of the singly tethered ligands for free permeability therein of the TTMs for affinity binding. The 3-D nature of the HPMP film provides high amplification of display, and the open nature of the matrix permits rapid elution of excess TTMs and other molecules. Importantly, the HPMP matrix layer, while providing amplification is also non-masking, being essentially transparent to detection methods. The combination of the reuseability, amplification and non-masking properties results in a very significant, many-fold increase in sensitivity and speed of screening assays.

    摘要翻译： 本发明涉及无阻挡构建和显示拴系的有机配体分子的方法和系统，更具体地涉及制备和使用锚定于各种功能化底物的薄膜，基本上非交联的亲水极性多官能化聚合物（HPMP），因此 HPMP形成薄膜基质层，提供相当于水溶液的独特的高度水合的高介电环境，用于将配体（L）与标记的靶分子（TTM）的亲和结合。 配体，特别是MERn配体文库，例如肽文库，通过“永久”强共价键单独连接到HPMP上，使得TTM的随后置换也不会使配体从HPMP中移位，从而使得HPMP拴系配体文库 可重复使用 HPMP薄膜的厚度约为200-2000，是高度可达的（对于TTM），并且允许单链系配体的灵活的3-D显示用于TTM的亲和结合的免费渗透性。 HPMP膜的3-D性质提供了显示的高扩增，并且基质的开放性质允许过量TTM和其它分子的快速洗脱。 重要的是，HPMP矩阵层虽然提供放大也是非掩蔽的，但对于检测方法基本上是透明的。 可再利用性，扩增和非掩蔽性质的组合导致筛选测定的灵敏度和速度非常显着，多重增加。

    Method and apparatus for peptide synthesis and screening
    2.
    发明授权
    Method and apparatus for peptide synthesis and screening 失效
    肽合成和筛选的方法和装置

    公开(公告)号：US5591646A

    公开(公告)日：1997-01-07

    申请号：US939065

    申请日：1992-09-02

    申请人： Derek Hudson ,  Charles R. Johnson ,  Lutz Giebel

    发明人： Derek Hudson ,  Charles R. Johnson ,  Lutz Giebel

    IPC分类号： B01D61/18 ,  B01J19/00 ,  B01L3/00 ,  C07K1/04 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  C40B60/14 ,  G01N33/543 ,  C07K17/00

    CPC分类号： B01L3/5025 ,  B01D61/18 ,  B01J19/0046 ,  B01L3/50255 ,  C07K1/045 ,  C07K1/047 ,  B01J2219/00416 ,  B01J2219/0043 ,  B01J2219/00497 ,  B01J2219/005 ,  B01J2219/00527 ,  B01J2219/00531 ,  B01J2219/00536 ,  B01J2219/00585 ,  B01J2219/0059 ,  B01J2219/00596 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/00617 ,  B01J2219/00619 ,  B01J2219/00626 ,  B01J2219/00641 ,  B01J2219/00659 ,  B01J2219/00664 ,  B01J2219/0072 ,  B01J2219/00722 ,  B01J2219/00725 ,  B01J2219/00731 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  C40B60/14 ,  Y02P20/582

    摘要： Method and apparatus for simple and rapid preparation of reusable, addressable surface-immobilized arrays of biomolecules (libraries) used for screening for interaction with any biologically significant target. A special plate having on its surface a plurality of discreet functionalized substrate areas, typically in arrays of 10.times.10 to 400.times.400, is provided for chemical synthesis or bonding thereon of desired families of biomolecules (e.g. peptides, DNA, RNA, oligosaccharides). In the case of peptides, such as hexapeptides, the resulting permanently hexapeptide-loaded plate is a reusable Addressable Synthetic Peptide Combinatorial Library (ASPCL), in which 1 to 3 (typically two) of the positions in the sequence are uniquely identified by the address location. Plate embodiments include substrates of physically bonded (e.g. glued) conventional particulate materials such as Pepsyn-K, or functionalizable films of linear or crosslinked polymers covalently attached to, or physically adhered to the plate surface. Spacer arm moieties may also be attached to the substrates. A unique multi-slot block assembly is used to prepare the ASPCLs. In library applications, for example determining peptides which bind to functional proteins (enzymes, receptors, antibodies), the substrate-bound peptides are assembled with several positions consisting of uniformly distributed equimolar mixtures of residues, and 2 separated or sequential positions uniquely identified by their spatial location on the substrate array, the "address". Following identification of the known residues giving the greatest affinity for the arrayed positions in the sequence, optimal binding for the complete peptide sequence is determined by an iterative process replacing formerly mixed positions with known AAs at unique addresses.

    摘要翻译： 用于简单快速地制备用于筛选与任何生物学显着靶物相互作用的生物分子（文库）的可重复使用的，可寻址的表面固定化阵列的方法和装置。 在其表面上具有通常为10×10 -4 400×400阵列的多个离散的官能化底物区域的特殊板，用于化学合成或在其上键合所需要的生物分子族（例如肽，DNA，RNA，寡糖）。 在肽（例如六肽）的情况下，所得到的永久性六肽加载的板是可重复使用的可寻址合成肽组合文库（ASPCL），其中序列中的1至3个（通常为2个）位置由地址唯一地标识 位置。 板实施方案包括物理结合（例如胶合）常规颗粒材料如Pepsyn-K的基材或共价附着或物理粘附到板表面的线性或交联聚合物的官能化膜。 间隔臂部分也可以附着到基底上。 使用独特的多槽块组件来准备ASPCL。 在文库应用中，例如确定与功能蛋白（酶，受体，抗体）结合的肽，底物结合的肽由几个位置组成，其中包含均匀分布的等摩尔残基混合物，以及由它们独特地鉴定的2个分离或连续位置 衬底阵列上的空间位置，“地址”。 在鉴定对序列中的排列位置具有最大亲和性的已知残基之后，通过迭代过程来确定完整肽序列的最佳结合，该迭代过程将以前与独特地址的已知AAs混合的位置替换。

    Pilot apparatus for peptide synthesis and screening
    3.
    发明授权
    Pilot apparatus for peptide synthesis and screening 失效
    用于肽合成和筛选的试验装置

    公开(公告)号：US5585275A

    公开(公告)日：1996-12-17

    申请号：US79741

    申请日：1993-06-18

    申请人： Derek Hudson ,  Charles R. Johnson ,  Lutz Giebel

    发明人： Derek Hudson ,  Charles R. Johnson ,  Lutz Giebel

    IPC分类号： B01D61/18 ,  B01J19/00 ,  B01L3/00 ,  C07K1/04 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  C40B60/14 ,  G01N33/543 ,  C07K17/00

    CPC分类号： B01L3/5025 ,  B01D61/18 ,  B01J19/0046 ,  B01L3/50255 ,  C07K1/045 ,  C07K1/047 ,  B01J2219/00416 ,  B01J2219/0043 ,  B01J2219/00459 ,  B01J2219/00497 ,  B01J2219/005 ,  B01J2219/00527 ,  B01J2219/00531 ,  B01J2219/00536 ,  B01J2219/00585 ,  B01J2219/0059 ,  B01J2219/00596 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/00617 ,  B01J2219/00619 ,  B01J2219/00626 ,  B01J2219/00641 ,  B01J2219/00659 ,  B01J2219/00664 ,  B01J2219/0072 ,  B01J2219/00722 ,  B01J2219/00725 ,  B01J2219/00731 ,  C40B40/06 ,  C40B40/10 ,  C40B40/12 ,  C40B60/14 ,  Y02P20/582

    摘要： Method and apparatus for simple and rapid preparation of reusable, addressable surface-immobilized arrays of biomolecules (libraries) used for screening for interaction with any biologically significant target. A special plate having on or in its surface a plurality of discreet functionalized substrate areas, typically in arrays of 10.times.10 to 400.times.400, is provided for chemical synthesis or bonding thereon of desired families of biomolecules (e.g. peptides, DNA, RNA, oligosaccharides). In the case of peptides, such as hexapeptides, the resulting permanently hexapeptide-loaded plate is a reusable Addressable Synthetic Peptide Combinatorial Library (ASPCL), in which 1 to 3 (typically two) of the positions in the sequence are uniquely identified by the address location. The preferred plate embodiment employs an HPMP wink of porous polyolefin removably received in holes in the plate. A unique multi-slot block assembly is used to prepare the ASPCLs. The wink carrier plate is also employed with a vacuum block system to assist in washing, deprotection, and probing. In library applications, for example determining peptides which bind to functional proteins (enzymes, receptors, antibodies), the substrate-bound peptides are assembled with several positions consisting of uniformly distributed equimolar mixtures of residues, and 2 separated or sequential positions uniquely identified by their spatial location on the substrate array, the "address". Following identification of the known residues giving the greatest affinity for the arrayed positions in the sequence, optimal binding for the complete peptide sequence is determined by an iterative process replacing formerly mixed positions with known AAs at unique addresses.

    摘要翻译： 用于简单快速地制备用于筛选与任何生物学显着靶物相互作用的生物分子（文库）的可重复使用的，可寻址的表面固定化阵列的方法和装置。 在其上或其表面上具有通常为10×10 -4 400×400阵列的多个离散功能化底物区域的特殊板被提供用于化学合成或在其上键合所需要的生物分子族（例如肽，DNA，RNA，寡糖）。 在肽（例如六肽）的情况下，所得到的永久性六肽加载的板是可重复使用的可寻址合成肽组合文库（ASPCL），其中序列中的1至3个（通常为2个）位置由地址唯一地标识 位置。 优选的板实施例使用可拆卸地容纳在板中的孔中的多孔聚烯烃的HPMP眨眼。 使用独特的多槽块组件来准备ASPCL。 眨眼承载板也与真空块系统一起使用以帮助洗涤，去保护和探测。 在文库应用中，例如确定与功能蛋白（酶，受体，抗体）结合的肽，底物结合的肽由几个位置组成，其中包含均匀分布的等摩尔残基混合物，以及由它们独特地鉴定的2个分离或连续位置 衬底阵列上的空间位置，“地址”。 在鉴定对序列中的排列位置具有最大亲和性的已知残基之后，通过迭代过程来确定完整肽序列的最佳结合，该迭代过程将以前与独特地址的已知AAs混合的位置替换。

    Method for production of acylthio derivatives
    4.
    发明授权
    Method for production of acylthio derivatives 失效
    酰基硫代衍生物的制备方法

    公开(公告)号：US06277957B1

    公开(公告)日：2001-08-21

    申请号：US09533095

    申请日：2000-03-23

    申请人： Derek Hudson ,  Stewart Thompson

    发明人： Derek Hudson ,  Stewart Thompson

    IPC分类号： C07C32720

    CPC分类号： C07K1/1077 ,  C07C327/22 ,  C07K1/086

    摘要： A method is provided which facilitates and enables the production of a wide range of complex conjugates composed of similar or dissimilar units linked together by amide bonds. Said method for the production of acylthio derivatives, R′—CO—SA, involves reaction of a carboxylate, R′—CO—O− (or carboxylic acid R′—CO—OH) with an iso-thiouronium derivative (bearing SA) in the presence of base. Nucleophilic counterion forms of the iso-thiouronium salts confer significant rate enhancement. The processes are simple, generally applicable, efficient, and do not require the employment of noxious reagents. The production of complex protein-like products by the intermediary of acylthio esters generated by the process of this invention, provides a method which is compatible with mild methods of chain assembly; and is preferably applied when the second component in the ligation bears an amino terminal cysteine residue.

    摘要翻译： 提供了一种方法，其促进并使得能够生产由通过酰胺键连接在一起的相似或不同单元组成的多种复合共轭体。 所述制备酰基硫代衍生物R'-CO-SA的方法包括羧酸酯R'-CO-O-（或羧酸R'-CO-OH）与异硫脲衍生物（带有SA）反应， 在基地的存在下。 异硫脲鎓盐的亲核抗衡离子形式具有显着的速率增加。 这些方法简单，一般适用，高效，不需要使用有毒试剂。 通过本发明方法产生的酰基硫代酯的中间产生复杂的蛋白质样产物提供了一种与温和的链组装方法相容的方法; 并且优选在连接中的第二组分具有氨基末端半胱氨酸残基时应用。

    Active esters for solid phase peptide synthesis
    5.
    发明授权
    Active esters for solid phase peptide synthesis 失效
    用于固相肽合成的活性酯

    公开(公告)号：US5233044A

    公开(公告)日：1993-08-03

    申请号：US766895

    申请日：1991-09-26

    申请人： Derek Hudson

    发明人： Derek Hudson

    IPC分类号： C07D231/22 ,  C07K1/08 ,  C07K1/10

    CPC分类号： C07K1/084 ,  C07D231/22 ,  C07K1/10

    摘要： Derivatives of 1-phenyl pyrazolin-5-one have many applications for biomolecule synthesis. Enol esters of protected amino acids made by the present process provide efficient coupling in solid-phase peptide synthesis. The 1-phenyl-pyrazolin-5-one derivatives are highly crystalline, stable, non-toxic and easy to prepare. Many possess self-indicating properties, facilitating spectrophotometric monitoring and automation of peptide synthesis.

    摘要翻译： 1-苯基吡唑啉-5-酮的衍生物具有生物分子合成的许多应用。 通过本方法制备的受保护氨基酸的烯醇酯在固相肽合成中提供有效的偶联。 1-苯基 - 吡唑啉-5-酮衍生物高度结晶，稳定，无毒，易于制备。 许多具有自我指示性质，促进分光光度监测和肽合成的自动化。

    Protecting groups for asparagine and glutamine in peptide synthesis
    8.
    发明授权
    Protecting groups for asparagine and glutamine in peptide synthesis 失效
    肽合成中天冬酰胺和谷氨酰胺的保护基

    公开(公告)号：US4935536A

    公开(公告)日：1990-06-19

    申请号：US316570

    申请日：1989-02-27

    申请人： Derek Hudson

    发明人： Derek Hudson

    IPC分类号： C07K1/06

    CPC分类号： C07K1/066 ,  Y02P20/55

    摘要： Trialkoxybenzyl (Taob) protected asparagine and glutamine, a method of synthesis and a method of use are provided. The Taob protected Asn and Gln have the following formulae: ##STR1## wherein Z is an alkyl group having from 1 to 10 carbon atoms; X and W are any .alpha.-protecting group which can be selectively removed while maintaining Taob intact; Y is H or any group sufficiently active or activatable to react with NH.sub.2 -- or NH.dbd. to generate an amide bond; n is 1 for asparagine or 2 for glutamine. These derivatives are stable in solution, have good solubility in organic solvents and couple directly without side reactions.

    摘要翻译： 提供三烷氧基苄基（Taob）保护的天冬酰胺和谷氨酰胺，合成方法和使用方法。 Taob保护的Asn和Gln具有下式：其中Z是具有1至10个碳原子的烷基; X和W是任何α保护基团，可以选择性地去除，同时保持Taob完整; Y是H或足够活性或可活化以与NH 2 - 或NH 3反应以产生酰胺键的任何基团; 天冬酰胺n为1，谷氨酰胺为2。 这些衍生物在溶液中是稳定的，在有机溶剂中具有良好的溶解性并直接偶联而无副反应。