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2. 发明授权

US06372712B1 Synthetic bifunctional molecules containing a drug moiety and presenter protein ligand 有权
标题翻译：含有药物部分和展示蛋白质配体的合成双功能分子
公开(公告)号：US06372712B1
公开(公告)日：2002-04-16
申请号：US09316932
申请日：1999-05-21
申请人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
发明人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
IPC分类号： A61K3800
CPC分类号： C12N9/90 , A61K38/00 , A61K47/54 , A61K47/552 , C07K5/1027 , C07K7/06 , C07K2319/00 , Y10S530/812
摘要： Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. The molecular weight of the bifunctional molecule is preferably less than about 5000 daltons, and the drug moiety may have a molecular weight of from about 50 to 2000 daltons. The drug moiety and presenter protein ligand may be covalently linked directly or through a linking group. The drug moiety binds to a drug target such as a protein and the presenter protein ligand binds to a presenter protein that is not the drug target such as extracellular or intracellular protein. Presenter proteins include peptidyl prolyl isomerase (FKBP), Heat Shock Protein 90 (Hsp90), steroid hormone receptors, cytoskeletal proteins, albumin and vitamin receptors. When the presenter protein is FKBP, ligands include FK506, rapamycin and cyclosporin A which may have an introduced functional group such as hydroxyl, amino, carboxyl, aldehyde, carbonate, carbamate, azide, thiol or ester for attaching the drug moiety. In the methods of use, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex such that the drug exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The methods and bifunctional molecules find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其在宿主生产二元配合物中的应用。双功能分子是药物部分和展示蛋白质配体的缀合物。双功能分子的分子量优选小于约5000道尔顿，并且药物部分可具有约50至2000道尔顿的分子量。药物部分和展示蛋白配体可以直接或通过连接基团共价连接。药物部分结合于药物靶，例如蛋白质，并且呈递者蛋白质配体结合不是药物靶点的呈递蛋白，例如细胞外或细胞内蛋白质。载体蛋白包括肽基脯氨酰异构酶（FKBP），热休克蛋白90（Hsp90），类固醇激素受体，细胞骨架蛋白，白蛋白和维生素受体。当本发明蛋白是FKBP时，配体包括FK506，雷帕霉素和环孢菌素A，其可以具有引入的官能团，例如羟基，氨基，羧基，醛，碳酸酯，氨基甲酸酯，叠氮化物，硫醇或酯，用于连接药物部分。在使用方法中，向宿主施用有效量的双功能分子。双功能分子与展示蛋白结合以产生二元复合物，使得药物与相应的游离药物相比显示出改善的亲和性，特异性或选择性中的至少一种。方法和双功能分子可用于各种治疗应用。

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