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

Autor:	Keough DT; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia., Wun SJ; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia., Baszczyňski O; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic., Eng WS; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia., Špaček P; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic., Panjikar S; Australian Synchrotron, ANSTO, 800 Blackburn Road, Clayton 3168, Victoria, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Australia., Naesens L; Katholieke Universiteit, Leuven, Rega Institute for Medical Research, Leuven 3000, Belgium., Pohl R; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic., Rejman D; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic., Hocková D; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6 CZ-166 10, Czech Republic., Ferrero RL; Hudson Institute of Medical Research, Clayton 3800, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton 3800, Australia.; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton 3800, Australia., Guddat LW; The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 May 13; Vol. 64 (9), pp. 5710-5729. Date of Electronic Publication: 2021 Apr 23.
DOI:	10.1021/acs.jmedchem.0c02184
Abstrakt:	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 K i 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.
Databáze:	MEDLINE
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