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

0556761 - ÚOCHB 2023 RIV US eng J - Journal Article
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
R&D Projects: GA ČR(CZ) GA19-07707S; GA MŠMT(CZ) EF16_019/0000759
Institutional support: RVO:61388963 ; RVO:60077344
Keywords : hypoxanthine-guanine phosporibosyltransferase * Plasmodium falciparum * Helicobacter pylori
OECD category: Medicinal chemistry
Impact factor: 7.3, year: 2022
Method of publishing: Limited access
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).
Permanent Link: http://hdl.handle.net/11104/0330950


Research data: PDB, PDB, PDB