First crystal structures of mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase: complexes with GMP and pyrophosphate and with acyclic nucleoside phosphonates ehose prodrugs have antituberculosis activity

Eng, Wai Soon, Hockova, Dana, Spacek, Petr, Janeba, Zlatko, West, Nicholas P., Woods, Kyra, Naesens, Lieve M. J., Keough, Dianne T. and Guddat, Luke W. (2015) First crystal structures of mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase: complexes with GMP and pyrophosphate and with acyclic nucleoside phosphonates ehose prodrugs have antituberculosis activity. Journal of Medicinal Chemistry, 58 11: 4822-4838. doi:10.1021/acs.jmedchem.5b00611


Author Eng, Wai Soon
Hockova, Dana
Spacek, Petr
Janeba, Zlatko
West, Nicholas P.
Woods, Kyra
Naesens, Lieve M. J.
Keough, Dianne T.
Guddat, Luke W.
Title First crystal structures of mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase: complexes with GMP and pyrophosphate and with acyclic nucleoside phosphonates ehose prodrugs have antituberculosis activity
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2015-06-11
Year available 2015
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.5b00611
Volume 58
Issue 11
Start page 4822
End page 4838
Total pages 17
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2016
Language eng
Formatted abstract
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 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 μM). In addition, the first crystal structures of MtHGPRT (2.03–2.76 Å 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.
Keyword Hypoxanthine guanine phosphoribosyltransferase
Steady state kinetics
Plasmodium falciparum
Xanthine phosphoribosyltransferase
Antimalarial chemotherapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 10 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 03 Jul 2015, 20:09:10 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences