Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics.
The purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite, Plasmodium falciparum. Acyclic nucleoside phosphonates (ANPs) are analogues of the nucleotide product of the reaction, comprising a purine base joined by a linker to a phosphonate moiety. K(i) values for 19 ANPs were determined for Pf HGXPRT and the corresponding human enzyme, HGPRT. Values for Pf HGXPRT were as low as 100 nM, with selectivity for the parasite enzyme of up to 58. Structures of human HGPRT in complex with three ANPs are reported. On binding, a large mobile loop in the free enzyme moves to partly cover the active site. For three ANPs, the IC(50) values for Pf grown in cell culture were 1, 14, and 46 microM, while the cytotoxic concentration for the first compound was 489 microM. These results provide a basis for the design of potent and selective ANP inhibitors of Pf HGXPRT as antimalarial drug leads.
Keough
Dianne T
DT
The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, 4072 QLD, Australia.
Hocková
Dana
D
Holý
Antonín
A
Naesens
Lieve M J
LM
Skinner-Adams
Tina S
TS
Jersey
John de
Jd
Guddat
Luke W
LW
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D011688:Purinones / Q000378:metabolism; D013379:Substrate Specificity
D000962:Antimalarials; D004791:Enzyme Inhibitors; D009705:Nucleosides; D063065:Organophosphonates; D011688:Purinones; D007041:Hypoxanthine Phosphoribosyltransferase