Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases

0556761 - ÚOCHB 2023 RIV US eng J - Článek v odborném periodiku
Klejch, Tomáš - Keough, D. T. - King, G. - Doleželová, Eva - Česnek, Michal - Buděšínský, Miloš - Zíková, Alena - Janeba, Zlatko - Guddat, L. W. - Hocková, Dana
Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases.
Journal of Medicinal Chemistry. Roč. 65, č. 5 (2022), s. 4030-4057. ISSN 0022-2623. E-ISSN 1520-4804
Grant CEP: GA ČR(CZ) GA19-07707S; GA MŠMT(CZ) EF16_019/0000759
Institucionální podpora: RVO:61388963 ; RVO:60077344
Klíčová slova: hypoxanthine-guanine phosporibosyltransferase * Plasmodium falciparum * Helicobacter pylori
Obor OECD: Medicinal chemistry
Impakt faktor: 7.3, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1021/acs.jmedchem.1c01881

Pathogens such as Plasmodium and Trypanosoma spp. are unable to synthesize purine nucleobases. They rely on the salvage of these purines and their nucleosides from the host cell to synthesize the purine nucleotides required for DNA/RNA production. The key enzymes in this pathway are purine phosphoribosyltransferases (PRTs). Here, we synthesized 16 novel acyclic nucleoside phosphonates, 12 with a chiral center at C-2′, and eight bearing a second chiral center at C-6′. Of these, bisphosphonate (S,S)-48 is the most potent inhibitor of the Plasmodium falciparum and P. vivax 6-oxopurine PRTs and the most potent inhibitor of two Trypanosoma brucei (Tbr) 6-oxopurine PRTs yet discovered, with Ki values as low as 2 nM. Crystal structures of (S,S)-48 in complex with human and Tbr 6-oxopurine PRTs show that the inhibitor binds to the enzymes in different conformations, providing an explanation for its potency and selectivity (i.e., 35-fold in favor of the parasite enzymes).
Trvalý link: http://hdl.handle.net/11104/0330950


Vědecká data: PDB, PDB, PDB