二糖类似物作为结核分枝杆菌中糖基转移酶的探针
Disaccharide analogs as probes for glycosyltransferases in Mycobacterium tuberculosis.
作者信息
Pathak Ashish K, Pathak Vibha, Seitz Lainne, Gurcha Sudagar S, Besra Gurdyal S, Riordan James M, Reynolds Robert C
机构信息
Drug Discovery Division, Southern Research Institute, PO Box 55305, Birmingham, AL 35255, USA.
出版信息
Bioorg Med Chem. 2007 Aug 15;15(16):5629-50. doi: 10.1016/j.bmc.2007.04.012. Epub 2007 Apr 10.
Glycosyltransferases (GTs) play a crucial role in mycobacterial cell wall biosynthesis and are necessary for the survival of mycobacteria. Hence, these enzymes are potential new drug targets for the treatment of tuberculosis (TB), especially multiple drug-resistant TB (MDR-TB). Herein, we report the efficient syntheses of Araf(alpha 1-->5)Araf, Galf(beta 1-->5)Galf, and Galf(beta 1-->6)Galf disaccharides possessing a 5-N,N-dimethylaminonaphthalene-1-sulfonamidoethyl (dansyl) unit that were prepared as fluorescent disaccharide acceptors for arabinosyl- and galactosyl-transferases, respectively. Such analogs may offer advantages relative to radiolabeled acceptors or donors for studying the enzymes and for assay development and compound screening. Additionally, analogs possessing a 5-azidonaphthalene-1-sulfonamidoethyl unit were prepared as photoaffinity probes for their potential utility in studying active site labeling of the GTs (arabinosyl and galactosyl) in Mycobacterium tuberculosis (MTB). Beyond their preparation, initial biological testing and kinetic analysis of these disaccharides as acceptors toward glycosyltransferases are also presented.
糖基转移酶（GTs）在分枝杆菌细胞壁生物合成中起关键作用，是分枝杆菌生存所必需的。因此，这些酶是治疗结核病（TB），尤其是耐多药结核病（MDR-TB）的潜在新药物靶点。在此，我们报告了分别作为阿拉伯糖基转移酶和半乳糖基转移酶的荧光二糖受体而制备的带有5-N，N-二甲基氨基萘-1-磺酰胺基乙基（丹磺酰基）单元的Araf（α1→5）Araf、Galf（β1→5）Galf和Galf（β1→6）Galf二糖的高效合成。相对于放射性标记的受体或供体，此类类似物在研究酶以及检测方法开发和化合物筛选方面可能具有优势。此外，还制备了带有5-叠氮萘-1-磺酰胺基乙基单元的类似物作为光亲和探针，用于研究其在结核分枝杆菌（MTB）中GTs（阿拉伯糖基和半乳糖基）活性位点标记方面的潜在用途。除了它们的制备方法外，还展示了这些二糖作为糖基转移酶受体的初步生物学测试和动力学分析。
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