4rhx

Publication Abstract from PubMed

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 Ki values as low as 0.69 muM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 muM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 muM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 A 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.

First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.,Eng WS, Hockova D, Spacek P, Janeba Z, West NP, Woods K, Naesens LM, Keough DT, Guddat LW J Med Chem. 2015 May 13. PMID:25915781^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.