First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have A

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• 作者：Wai Soon Eng ; Dana Hockov谩 ; Petr 艩pa膷ek ; Zlatko Janeba ; Nicholas P. West ; Kyra Woods ; Lieve M. J. Naesens ; Dianne T. Keough ; Luke W. Guddat
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4822-4838
• 全文大小：843K
• ISSN：1520-4804

文摘

Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with K_i values as low as 0.69 渭M. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC₅₀ values as low as 4.5 渭M and possess low cytotoxicity in mammalian cells (CC₅₀ values as high as >300 渭M). In addition, the first crystal structures of MtHGPRT (2.03鈥?.76 脜 resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.