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    Hemoglobins with intersubunit dislufide bonds
    5.
    发明授权
    Hemoglobins with intersubunit dislufide bonds 失效
    血红蛋白与次间隔不同的结合

    公开(公告)号：US6124114A

    公开(公告)日：2000-09-26

    申请号：US450900

    申请日：1995-05-26

    申请人： Stephen J. Hoffman ,  Kiyoshi Nagai

    发明人： Stephen J. Hoffman ,  Kiyoshi Nagai

    IPC分类号： A61K38/00 ,  C07K14/805 ,  C12P21/06 ,  C07H17/00

    CPC分类号： C07K14/805 ,  A61K38/00 ,  C07K2319/00 ,  Y10S514/832 ,  Y10S514/833

    摘要： Cysteine substitution mutants of alpha and/or beta globin mutants are produced by recombinant DNA techniques and used in the construction, intracellularly or otherwise, of mutant hemoglobins in which alpha- and beta-globin like subunits are crosslinked by disulfide bonds. Solutions of these mutant hemoglobins are used as blood substitutes.Preferably, these mutant hemoglobins contain further mutations which reduce their affinity for oxygen.Hemoglobins are preferably obtained by recombinant DNA techniques. Both alpha and beta globin chains can now be readily expressed, making possible the commercial production of wholly artificial hemoglobin, whether conventional or mutant in form. Solutions of wholly artificial hemoglobins are also used as blood substitutes. Expression of the alpha glolbin gene was substantially improved by means of a beta globin gene "header".

    摘要翻译： α和/或β球蛋白突变体的半胱氨酸取代突变体通过重组DNA技术产生并用于构建，细胞内或其它突变体血红蛋白，其中α和β-珠蛋白样亚基通过二硫键交联。 这些突变体血红蛋白的溶液用作血液代用品。 优选地，这些突变体血红蛋白含有进一步降低其对氧的亲和力的突变。 血红蛋白优选通过重组DNA技术获得。 现在可以容易地表达α和β球蛋白链，使得完全人造血红蛋白的商业生产成为可能，无论是常规的还是突变形式。 完全人造血红蛋白的溶液也用作血液代用品。 α球蛋白基因的表达通过β球蛋白基因“头”显着改善。

    Hemoglobins with intersubunit disulfide bonds
    6.
    发明授权
    Hemoglobins with intersubunit disulfide bonds 失效
    血红蛋白与亚基间二硫键

    公开(公告)号：US5776890A

    公开(公告)日：1998-07-07

    申请号：US453666

    申请日：1995-05-30

    申请人： Stephen J. Hoffman ,  Kiyoshi Nagai

    发明人： Stephen J. Hoffman ,  Kiyoshi Nagai

    IPC分类号： A61K38/00 ,  C07K14/805

    CPC分类号： C07K14/805 ,  A61K38/00 ,  C07K2319/00 ,  Y10S514/832 ,  Y10S514/833

    摘要： Cysteine substitution mutants of alpha and/or beta globin mutants are produced by recombinant DNA techniques and used in the construction, intracellularly or otherwise, of mutant hemoglobins in which alpha- and beta-globin like subunits are crosslinked by disulfide bonds. Solutions of these mutant hemoglobins are used as blood substitutes. Preferably, these mutant hemoglobins contain further mutations which reduce their affinity for oxygen. Hemoglobins are preferably obtained by recombinant DNA techniques. Both alpha and beta globin chains can now be readily expressed, making possible the commercial production of wholly artificial hemoglobin, whether conventional or mutant in form. Solutions of wholly artificial hemoglobins are also used as blood substitutes. Expression of the alpha globin gene was substantially improved by means of a beta globin gene "header".

    摘要翻译： α和/或β球蛋白突变体的半胱氨酸取代突变体通过重组DNA技术产生并用于构建，细胞内或其它突变体血红蛋白，其中α和β-珠蛋白样亚基通过二硫键交联。 这些突变体血红蛋白的溶液用作血液代用品。 优选地，这些突变体血红蛋白含有进一步降低其对氧的亲和力的突变。 血红蛋白优选通过重组DNA技术获得。 现在可以容易地表达α和β球蛋白链，使得完全人造血红蛋白的商业生产成为可能，无论是常规的还是突变形式。 完全人造血红蛋白的溶液也用作血液代用品。 通过β球蛋白基因“头”，α球蛋白基因的表达显着改善。

    Co-expression of alpha and beta globins
    7.
    发明授权
    Co-expression of alpha and beta globins 失效

    公开(公告)号：US5798227A

    公开(公告)日：1998-08-25

    申请号：US446105

    申请日：1995-05-19

    申请人： Stephen J. Hoffman ,  Douglas L. Looker ,  Gary L. Stetler ,  Michael Wagenbach

    发明人： Stephen J. Hoffman ,  Douglas L. Looker ,  Gary L. Stetler ,  Michael Wagenbach

    IPC分类号： A61K38/16 ,  A61K38/00 ,  A61K47/48 ,  A61P7/08 ,  C07K20060101 ,  C07K1/113 ,  C07K14/805 ,  C12N15/00 ,  C12N15/09 ,  C12N15/12 ,  C12N15/81 ,  C12P21/02 ,  C12R1/19 ,  C12R1/91 ,  C12P21/06 ,  C12N1/20 ,  C12P21/04

    CPC分类号： C07K14/805 ,  A61K47/48307 ,  C12N15/81 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/50 ,  C07K2319/92

    摘要： The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained. We further describe the production of tetrameric human hemoglobin and di-alpha/beta.sub.2 hemoglobin in the yeast Saccharomyces cerevisiae. The synthesis of the protein is directed by a synthetic promotor consisting of two functional parts, an upstream activator sequence (UAS) that confers inducible transcription by galactose from a consensus yeast transcriptional initiation site. The expression construct is designed such that translation is expected to initiate at the same position as the human wild-type genes for .alpha.- and .beta.-globin. Three different types of expression vectors have been used: (1) .alpha.-globin and .beta.-globin contained on two separate plasmids (pGS4688 and pGS4988) in a diploid yeast strain; (2) .alpha.-globin and .beta.-globin each contained on a single plasmid (pGS289 and pGS389) and expressed in either haploid or diploid strains; and (3) di-alpha-globin and beta globin contained on a single plasmid (pGS 3089)and expressed in haploid strains. Finally, we describe the co-expression of alpha and beta globin chains. The chains are folded together and combined intracellularly with heme to form active tetrameric hemoglobin. The hemoglobin may be recovered from the cells' soluble fraction. The invention thus obviates the need to express alpha and beta globin separately, solubilize, renature and purify them, and combine them in vitro with heme to obtain an artificial hemoglobin. By way of comparison, the separately expressed beta globin known in the art is deposited in inclusion bodies. Polycistronic co-expression of alpha and beta globins is particularly preferred.

    DNA encoding fused di-alpha globins and use thereof
    10.
    发明授权
    DNA encoding fused di-alpha globins and use thereof 失效
    编码融合二-α球蛋白的DNA及其用途

    公开(公告)号：US06828125B1

    公开(公告)日：2004-12-07

    申请号：US08453485

    申请日：1995-05-30

    申请人： Stephen J. Hoffman ,  Douglas L. Looker ,  Kiyoshi Nagai

    发明人： Stephen J. Hoffman ,  Douglas L. Looker ,  Kiyoshi Nagai

    IPC分类号： C12P2106

    CPC分类号： C07K14/805 ,  A61K38/00 ,  A61K47/6445 ,  C07K2319/00 ,  C12N15/81

    摘要： The alpha subunits of hemoglobin, which in nature are formed as separate polypeptide chains which bind noncovalently to the beta subunits, are here provided in the form of the novel molecule di-alpha globin, a single polypeptide chain defined by connecting the two alpha subunits either directly via peptide bond or indirectly by a flexible amino acid or peptide linker. Di-alpha globin may be combined in vivo or in vitro with beta globin and heme to form hemoglobin. Di-alpha globin is expressed by recombinant DNA techniques. Di-beta globin may be similarly obtained.

    摘要翻译： 在本文中，血红蛋白的α亚基本质上被形成为与β-亚基非共价结合的分离的多肽链，这里以新分子二-α球蛋白的形式提供，单链多肽链通过将两个α亚基连接而定义 直接通过肽键或通过柔性氨基酸或肽接头间接。 Di-α珠蛋白可以在体内或体外与β球蛋白和血红素组合以形成血红蛋白。 Di-α球蛋白通过重组DNA技术表达。 可以类似地获得二β-珠蛋白。