Helicobacter pylori Xanthine–Guanine–Hypoxanthine Phosphoribosyltransferase—A Putative Target for Drug Discovery against Gastrointestinal Tract Infections

0542267 - ÚOCHB 2022 RIV US eng J - Článek v odborném periodiku
Keough, D. T. - Wun, J. S. - Baszczyňski, Ondřej - Eng, W. S. - Špaček, Petr - Panjikar, S. - Naesens, L. - Pohl, Radek - Rejman, Dominik - Hocková, Dana - Ferrero, R. L. - Guddat, L. W.
Helicobacter pylori Xanthine–Guanine–Hypoxanthine Phosphoribosyltransferase—A Putative Target for Drug Discovery against Gastrointestinal Tract Infections.
Journal of Medicinal Chemistry. Roč. 64, č. 9 (2021), s. 5710-5729. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR(CZ) GA19-07707S
Institucionální podpora: RVO:61388963
Klíčová slova: XGHPRT * inhibitor * phosphonate * nucleotide
Obor OECD: Organic chemistry
Impakt faktor: 8.039, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1021/acs.jmedchem.0c02184

Helicobacter pylori (Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world’s population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine–guanine–hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 μM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.
Trvalý link: http://hdl.handle.net/11104/0319726