Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 5, Pages 4030-4057Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01881
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Funding
- Czech Science Foundation [19-07707S]
- ERD funds [CZ.02.1.01/0.0/0.0/16_019/0000759]
- National Health and Medical Research Council, Australia [1147368]
- subvention for development of research organization (Institute of Organic Chemistry and Biochemistry) [RVO 61388963]
- National Health and Medical Research Council of Australia [1147368] Funding Source: NHMRC
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Pathogens rely on host cells to salvage purines and nucleosides for nucleotide synthesis. Researchers synthesized 16 novel acyclic nucleoside phosphonates and found that bisphosphonate (S,S)-48 is the most potent inhibitor of Plasmodium, Trypanosoma, and human enzymes, with different conformational binding to parasite and human enzymes.
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 K-i 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).
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