Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.

0585825 - ÚOCHB 2025 RIV US eng J - Journal Article
Keough, D. T. - Petrová, Magdalena - King, G. - Kratochvil, Michal - Pohl, Radek - Doležalová, E. - Ziková, A. - Guddat, L. W. - Rejman, Dominik
Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.
Journal of Medicinal Chemistry. Roč. 67, č. 9 (2024), s. 7158-7175. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) LX22NPO5103
Institutional support: RVO:61388963
Keywords : trypanosomiasis * hxgprt * prolinol nucleoside bisphosphonate
OECD category: Organic chemistry
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.4c00021

Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax, Trypanosoma brucei, Mycobacterium tuberculosis, and Helicobacter pylori. Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have Ki values ranging from 3 nM to >10 muM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against TBr in cell culture, a prodrug exhibited an EC50 of 10 muM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.
Permanent Link: https://hdl.handle.net/11104/0353500