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    Matrix metalloproteinase inhibitor peptides
    1.
    发明授权
    Matrix metalloproteinase inhibitor peptides 失效
    基质金属蛋白酶抑制剂肽

    公开(公告)号：US5595885A

    公开(公告)日：1997-01-21

    申请号：US39525

    申请日：1993-03-29

    申请人： William G. Stetler-Stevenson ,  Lance A. Liotta ,  Henry C. Krutzsch

    发明人： William G. Stetler-Stevenson ,  Lance A. Liotta ,  Henry C. Krutzsch

    IPC分类号： A61K35/12 ,  A61K38/00 ,  A61K38/55 ,  A61K39/395 ,  A61K48/00 ,  A61K49/00 ,  A61P37/00 ,  C07K1/16 ,  C07K1/22 ,  C07K7/08 ,  C07K14/00 ,  C07K14/81 ,  C07K16/00 ,  C12N1/21 ,  C12N15/09 ,  C12N15/15 ,  C12P21/02 ,  C12R1/91 ,  G01N33/53 ,  G01N33/573 ,  C12N15/00

    CPC分类号： C07K14/8146 ,  A61K38/00

    摘要： The present invention is an isolated protein of 21,600 Da which binds to both latent and activated type IV collagenase with high affinity at 1:1 molar stoichiometry, thereby abolishing enzyme activity. The protein is purified by affinity chromatography on solid phase metalloproteinase, or solid phase metalloproteinase substrates which bind the enzyme-inhibitor complex. The complete primary structure of this protein (initially called CSC-21K), as determined by sequencing overlapping peptides spanning the entire protein, reveals homology with a protein called TIMP, Tissue Inhibitor of Metalloproteinases. In addition, a cDNA for this novel inhibitor, now designated TIMP-2, was cloned from a melanoma cell and its sequence was compared with that of human TIMP-1. Northern blots of melanoma cell mRNA showed two distinct transcripts of 0.9 kb and 3.5 kb which are down-regulated by transforming growth factor-.beta., and are unchanged by phorbol ester treatment. The inhibitor of the present invention may be used for treatment of pathologic conditions resulting from inappropriate degradation of extracellular matrix molecules by matrix metalloproteinases, such as metastatic neoplasia, myocardial infarction, and arthritis. Therapeutic treatments using this inhibitor may include formulations for inhalation and inclusion complexes adapted for buccal or sublingual administration, or administration of a recombinant DNA molecule which expresses a DNA segment that encodes the matrix metalloproteinase inhibitor of this invention.

    摘要翻译： 本发明是21,600Da的分离蛋白，其以1:1的摩尔化学计量比以高亲和力结合潜在和活化的IV型胶原酶，从而消除酶活性。 蛋白质通过固相金属蛋白酶上的亲和层析或结合酶抑制剂复合物的固相金属蛋白酶底物纯化。 通过测序跨越整个蛋白质的重叠肽测定，该蛋白质（最初称为CSC-21K）的完整的一级结构显示与称为TIMP，金属蛋白酶组织抑制剂的蛋白质的同源性。 此外，从黑素瘤细胞中克隆了此新型抑制剂cDNA（现称为TIMP-2），并将其序列与人TIMP-1进行比较。 黑色素瘤细胞mRNA的Northern印迹显示0.9kb和3.5kb的两个不同的转录物，其通过转化生长因子-β下调，并且通过佛波酯处理不变。 本发明的抑制剂可用于治疗由基质金属蛋白酶如转移性肿瘤，心肌梗塞和关节炎不适当地降解细胞外基质分子而导致的病理状况。 使用该抑制剂的治疗性治疗可以包括适于口腔或舌下施用的吸入制剂和包合配合物，或者给予表达编码本发明的基质金属蛋白酶抑制剂的DNA区段的重组DNA分子。

    Metalloproteinase peptides
    2.
    发明授权
    Metalloproteinase peptides 失效
    金属蛋白酶

    公开(公告)号：US5698671A

    公开(公告)日：1997-12-16

    申请号：US284721

    申请日：1994-08-02

    申请人： William G. Stetler-Stevenson ,  Lance A. Liotta ,  Henry C. Krutzsch

    发明人： William G. Stetler-Stevenson ,  Lance A. Liotta ,  Henry C. Krutzsch

    IPC分类号： A61K38/00 ,  C07K14/81 ,  C07K7/00

    CPC分类号： C07K14/8146 ,  A61K38/00

    摘要： Inappropriate degradation of extracellular matrix molecules by metalloproteinases plays an important role in a wide variety of pathologic conditions including neoplasia and arthritis. The present invention is an isolated protein of approximately 23,000 daltons in size which binds to metalloproteinases with high affinity, can be purified using affinity chromatography on solid phase metalloproteinases, and is potentially useful for therapy of pathologic conditions involving the inappropriate production of metalloproteinases. This protein is characterized by the presence of the following amino acid sequences: CSCSPVHPQQAFCNADVVIRAKAVSEKEVDSGNPIYGNNI KDIEFIYTAPSEAVCGVELDVEGK KRHITLCDFIVPWDTLSTTQKKSLNHRYQQGCEECKITRCPMIPCYISSPDECLWTDTVV KFFACIKRHITLCDFIVPWSQIADXLSS With the positions of the cysteine residues and associated disulfide bridges required for biologic activity.

    摘要翻译： 金属蛋白酶对细胞外基质分子的不适当降解在包括肿瘤形成和关节炎在内的多种病理状况中起重要作用。 本发明是大约23,000道尔顿的分离的蛋白质，其以高亲和力结合金属蛋白酶，可以使用固相金属蛋白酶上的亲和层析纯化，并且可能用于治疗涉及金属蛋白酶不适当的病理状况。 该蛋白的特征在于存在以下氨基酸序列：CSCSPVHPQQAFCNADVVIRAKAVSEKEVDSGNPIYGNNI KDIEFIYTAPSEAVCGVELDVEGK KRHITLCDFIVPWDTLSTTQKKSLNHRYQQGCEECKITRCPMIPCYISSPDECLWTDTVV KFFACIKRHITLCDFIVPWSQIADXLSS具有生物活性所需的半胱氨酸残基和相关二硫键的位置。

    Matrix metalloproteinase peptides: role in diagnosis and therapy
    4.
    发明授权
    Matrix metalloproteinase peptides: role in diagnosis and therapy 失效
    基质金属蛋白酶肽：在诊断和治疗中的作用

    公开(公告)号：US5585356A

    公开(公告)日：1996-12-17

    申请号：US289825

    申请日：1994-08-12

    申请人： Lance A. Liotta ,  William G. Stetler-Stevenson ,  Henry C. Krutsch

    发明人： Lance A. Liotta ,  William G. Stetler-Stevenson ,  Henry C. Krutsch

    IPC分类号： G01N33/53 ,  A61K9/08 ,  A61K38/55 ,  A61P19/02 ,  A61P35/00 ,  A61P43/00 ,  C07H21/04 ,  C07K7/06 ,  C07K7/08 ,  C07K14/00 ,  C07K14/81 ,  C07K16/00 ,  C07K16/38 ,  C07K17/00 ,  C12N5/10 ,  C12N9/99 ,  C12N15/09 ,  G01N33/573 ,  A61K38/00

    CPC分类号： C07K14/8146 ,  G01N33/573 ,  Y10S530/806 ,  Y10S530/81

    摘要： A family of metalloproteinases exist which cleave extracellular matrix molecules. These metalloproteinases are secreted in a latent inactive form and require activation in order to specifically cleave the preferred substrate. A series of peptides have been prepared based on the complete sequence analysis of type IV procollagenase. Peptide inhibitors were synthesized which correspond to cysteine repeat regions and histidine containing regions; the mechanism of action of these peptides involves inhibition of binding of the enzyme to the substrate. Peptide inhibitors were synthesized which correspond to the peptide cleaved off during activation, and constitute a novel class of metalloproteinase inhibitors. These inhibitors are members of a series of peptides which contain the core amino acid sequence RKPRC or analogs thereof. The cysteine residue is required for activity. Affinity purified antibodies directed against specific peptides can be used to a) detect any general metalloproteinase enzyme with the sequence in part VAAHE or PRCGNPD, and distinguish it from other known members of the metalloproteinase family, b) block functional domains resulting in the inhibition of enzyme activity, and c) distinguish latent from activated forms of the enzyme.

    摘要翻译： 存在切割细胞外基质分子的金属蛋白酶家族。 这些金属蛋白酶以潜伏活性形式分泌并需要活化以特异性切割优选的底物。 已经基于IV型原胶原酶的完整序列分析制备了一系列肽。 合成肽抑制剂，其对应于半胱氨酸重复区域和组氨酸区域; 这些肽的作用机制涉及抑制酶与底物的结合。 合成肽抑制剂，其对应于在活化期间切除的肽，并构成新型的金属蛋白酶抑制剂。 这些抑制剂是含有核心氨基酸序列RKPRC或其类似物的一系列肽的成员。 活性需要半胱氨酸残基。 针对特异性肽的亲和纯化抗体可用于a）用部分VAAHE或PRCGNPD中的序列检测任何一般金属蛋白酶，并将其与其他已知的金属蛋白酶家族成员区分开，b）阻断功能结构域，导致酶的抑制 活性，和c）区分潜在和酶的活化形式。

    Vasoregulating compounds and methods of their use
    6.
    发明授权
    Vasoregulating compounds and methods of their use 失效
    减压化合物及其使用方法

    公开(公告)号：US07364719B2

    公开(公告)日：2008-04-29

    申请号：US10529118

    申请日：2003-10-03

    申请人： Frank Cuttitta ,  Alfredo Martinez ,  William G. Stetler-Stevenson ,  Edward J. Unsworth ,  Juan M. Saavedra

    发明人： Frank Cuttitta ,  Alfredo Martinez ,  William G. Stetler-Stevenson ,  Edward J. Unsworth ,  Juan M. Saavedra

    IPC分类号： A61K49/00

    CPC分类号： A61K38/22 ,  A61K31/137 ,  G01N33/5088 ,  G01N2500/00

    摘要： Methods and compounds are described for regulating blood pressure in a subject. Specific embodiments are methods for reversing vasodilation of blood vessels, by administering to a subject a therapeutically effective amount peptide AM(11-22). The vasoconstrictor can be used for a variety of purposes, including hemostasis or the treatment of shock, for example vasodilatory shock syndromes such as septic shock. Other specific embodiments are methods for reversing vasoconstriction of blood vessels, by administering to a subject a therapeutically effect amount of an inhibitor of AM(11-22), sufficient to reduce hypertension in the subject. Compounds and pharmaceutical compositions are also provided, as are kits.

    摘要翻译： 描述了用于调节受试者血压的方法和化合物。 具体实施方案是通过向受试者施用治疗有效量的肽AM（11-22）来逆转血管的血管舒张的方法。 血管收缩剂可用于各种目的，包括止血或治疗休克，例如血管舒张性休克综合征，如脓毒性休克。 其他具体实施方案是通过向受试者施用足以降低受试者的高血压的治疗有效量的AM（11-22）抑制剂来逆转血管的血管收缩的方法。 还提供了化合物和药物组合物，试剂盒也是如此。

    Method for measuring type IV collagenase
    9.
    发明授权
    Method for measuring type IV collagenase 失效
    IV型胶原酶测定方法

    公开(公告)号：US5869277A

    公开(公告)日：1999-02-09

    申请号：US789652

    申请日：1991-11-08

    申请人： William G. Stetler-Stevenson ,  Lance Liotta

    发明人： William G. Stetler-Stevenson ,  Lance Liotta

    IPC分类号： G01N33/53 ,  G01N33/543 ,  G01N33/547 ,  G01N33/573 ,  G01N33/68 ,  C12Q1/28 ,  C12Q1/37

    CPC分类号： G01N33/6887 ,  G01N33/573

    摘要： The present invention relates to the development of a modified substrate capture immunoassay useful in the detection of a neutral metalloproteinase enzyme, type IV collagenase. Capture and immobilization of this enzyme can be achieved by coating the microtiter plate with gelatin, an alternative substrate for this enzyme. The captured enzyme can then be detected by affinity purified rabbit anti-type IV collagenase antibodies prepared against synthetic peptides from the amino terminus of the enzyme. Soluble type IV collagenase can readily be detected in samples known to contain this enzyme. Using purified enzyme this assay method can detect less than 50 ng of latent type IV collagenase. Using EDTA, an inhibitor of this metalloproteinase, gelatin binding can be shown to be independent of catalytic activity.

    摘要翻译： 本发明涉及用于检测中性金属蛋白酶IV型胶原酶的修饰的底物捕获免疫测定法的开发。 该酶的捕获和固定可以通过用明胶（该酶的替代底物）包被微量滴定板来实现。 然后可以通过从酶的氨基末端制备的针对合成肽的亲和纯化的兔抗IV型胶原酶抗体来检测所捕获的酶。 可溶性IV型胶原酶可以在已知含有该酶的样品中容易地检测。 使用纯化酶，该测定方法可以检测到低于50ng的潜伏型IV胶原酶。 使用EDTA，这种金属蛋白酶的抑制剂，明胶结合可以显示与催化活性无关。