Journal of medicinal chemistry, 2015-06, Vol.58 (11), p.4822-4838
2015
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- Autor(en) / Beteiligte
- Titel
- First Crystal Structures of Mycobacterium tuberculosis 6‑Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity
- Ist Teil von
- Journal of medicinal chemistry, 2015-06, Vol.58 (11), p.4822-4838
- Ort / Verlag
- United States: American Chemical Society
- Erscheinungsjahr
- 2015
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2623eISSN: 1520-4804DOI: 10.1021/acs.jmedchem.5b00611Titel-ID: cdi_proquest_miscellaneous_1687995697
- Format
- –
- Schlagworte
- Amino Acid Sequence, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Antitubercular Agents - chemistry, Antitubercular Agents - pharmacology, Catalytic Domain, Cell Proliferation - drug effects, Crystallography, X-Ray, Diphosphates - chemistry, Diphosphates - metabolism, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Guanosine Monophosphate - chemistry, Guanosine Monophosphate - metabolism, Humans, Hypoxanthine Phosphoribosyltransferase - chemistry, Hypoxanthine Phosphoribosyltransferase - metabolism, Lung Neoplasms - drug therapy, Lung Neoplasms - pathology, Models, Molecular, Molecular Sequence Data, Molecular Structure, Mycobacterium tuberculosis - drug effects, Mycobacterium tuberculosis - enzymology, Organophosphonates - chemistry, Organophosphonates - metabolism, Prodrugs - chemistry, Prodrugs - pharmacology, Protein Conformation, Sequence Homology, Amino Acid, Structure-Activity Relationship, Tuberculosis - drug therapy, Tuberculosis - microbiology, Tumor Cells, Cultured