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

0445809 - ÚOCHB 2016 RIV US eng J - Článek v odborném periodiku
Eng, W. S. - Hocková, Dana - Špaček, Petr - Janeba, Zlatko - West, N. P. - Woods, K. - Naesens, L. M. J. - Keough, D. T. - Guddat, L. W.
First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.
Journal of Medicinal Chemistry. Roč. 58, č. 11 (2015), s. 4822-4838. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR GAP207/11/0108; GA MV VG20102015046
Institucionální podpora: RVO:61388963
Klíčová slova: enzyme inhibitors * nucleotide analogues * tuberculosis * crystal structures
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 5.589, rok: 2015

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 mu M. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 mu M and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 mu M). In addition, the first crystal structures of MtHGPRT (2.03-2.76 angstrom 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.
Trvalý link: http://hdl.handle.net/11104/0247858