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First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity
WS. Eng, D. Hocková, P. Špaček, Z. Janeba, NP. West, K. Woods, LM. Naesens, DT. Keough, LW. Guddat,
Journal of medicinal chemistry.
2015 ;
58 (11) :
4822-38.
[pub] 20150513
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc15031371
- MeSH
- Antitubercular Agents chemistry pharmacology MeSH
- Diphosphates chemistry metabolism MeSH
- Hypoxanthine Phosphoribosyltransferase chemistry metabolism MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Crystallography, X-Ray MeSH
- Guanosine Monophosphate chemistry metabolism MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Sequence Data MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis drug effects enzymology MeSH
- Tumor Cells, Cultured MeSH
- Lung Neoplasms drug therapy pathology MeSH
- Organophosphonates chemistry metabolism MeSH
- Prodrugs chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Amino Acid Sequence MeSH
- Sequence Homology, Amino Acid MeSH
- Tuberculosis drug therapy microbiology MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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