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

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).