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2. 发明授权

US07338932B2 Methods of modulating functions of polypeptide GalNAc-transferases and of screening test substances to find agents herefor, pharmaceutical compositions comprising such agents and the use of such agents for preparing medicaments 有权
标题翻译：调节多肽GalNAc转移酶的功能和筛选测试物质以找到本发明的药剂的方法，包含这些药剂的药物组合物以及这些药物用于制备药物的用途
公开(公告)号：US07338932B2
公开(公告)日：2008-03-04
申请号：US10292896
申请日：2002-11-12
申请人： Henrik Clausen , Eric Paul Bennett , Helle Hassan , Celso Albuquerque Reis
发明人： Henrik Clausen , Eric Paul Bennett , Helle Hassan , Celso Albuquerque Reis
IPC分类号： A61K38/16 , A61K38/00 , C07H1/00 , C07H5/04 , C07H19/00
CPC分类号： A61K38/14 , A61K38/1709 , C12N9/1051 , C12Q1/48 , G01N2500/00 , G01N2500/10
摘要： Attachment of O-glycans to proteins is controlled by a large family of homologous polypeptide GalNAc-transferases. Polypeptide GalNAc-transferases contain a C-terminal sequence with similarity to lectins. This invention discloses that the putative lectin domains of GalNAc-transferase isoforms, GalNAc-T4, -T7, -T2, and -T3, are functional and recognize carbohydrates, glycopeptides, and peptides and discloses the lectin domains of GalNAc-T1-T16. These lectin domains have different binding specificities and modulate the functions of GalNAc-transferase isoforms differently. Novel methods for identification of inhibitors or modulators of binding activities mediated by lectin domains of polypeptide GalNAc-transferases are disclosed. Direct binding activity of GalNAc-transferase lectins has been demonstrated for the first time and methods to measure lectin mediated binding of isolated lectins or enzymes with lectin domains are disclosed. The present invention specifically discloses a novel selective inhibitor of polypeptide GalNAc-transferase lectin domains, which provides a major advancement in that this inhibitor and related inhibitors sharing common characteristics of activity bind lectin domains without serving as acceptor substrate for glycosyltransferases involved in synthesis of O-glycans. This inhibitor is represented by the β-anomeric configuration of GalNAc-benzyl, GalNAcβ-benzyl. Methods for inhibiting intracellular transport, cell surface expression, and secretion of mucins and O-glycosylated glycoproteins without affecting O-glycosylation processing are disclosed using the novel selective inhibitor identified.
摘要翻译： O-聚糖对蛋白质的附着由大量的同源多肽GalNAc转移酶家族控制。多肽GalNAc转移酶含有与凝集素相似的C-末端序列。本发明公开了GalNAc转移酶同工型，GalNAc-T4，-T7，-T2和-T3的推定凝集素结构域是功能性的并识别碳水化合物，糖肽和肽，并公开了GalNAc-T1-T16的凝集素结构域。这些凝集素结构域具有不同的结合特异性，并且不同地调节GalNAc转移酶同工型的功能。公开了用于鉴定由多肽GalNAc转移酶的凝集素结构域介导的结合活性的抑制剂或调节剂的新方法。已经首次证明了GalNAc转移酶凝集素的直接结合活性，并且公开了测定凝血素介导的分离的凝集素或酶与凝集素结构域的结合的方法。本发明特别公开了一种新型多肽GalNAc转移酶凝集素结构域的选择性抑制剂，其提供了主要进展，即该抑制剂和相关抑制剂共享活性的共同特征结合凝集素结构域，而不用作参与合成O-糖蛋白的糖基转移酶的受体底物，聚糖。该抑制剂由GalNAc-苄基，GalNAcβ-苄基的β-异头构型表示。使用鉴定的新型选择性抑制剂公开了抑制细胞内转运，细胞表面表达和分泌粘蛋白和O-糖基化糖蛋白的方法，而不影响O-糖基化处理。

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