PMID:19527031

Citation	Keough, DT, Hocková, D, Holý, A, Naesens, LM, Skinner-Adams, TS, Jersey, J and Guddat, LW (2009) Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics. J. Med. Chem. 52:4391-9
Abstract	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.
Links	PubMed Online version:10.1021/jm900267n
Keywords	Animals; Antimalarials/chemical synthesis; Antimalarials/chemistry; Antimalarials/pharmacology; Antimalarials/toxicity; Catalytic Domain; Cell Line, Tumor; Cell Survival/drug effects; Crystallography, X-Ray; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/toxicity; Erythrocytes/drug effects; Erythrocytes/parasitology; Humans; Hypoxanthine Phosphoribosyltransferase/antagonists & inhibitors; Hypoxanthine Phosphoribosyltransferase/chemistry; Inhibitory Concentration 50; Models, Molecular; Nucleosides/chemistry; Phosphonic Acids/chemical synthesis; Phosphonic Acids/chemistry; Phosphonic Acids/pharmacology; Phosphonic Acids/toxicity; Plasmodium falciparum/drug effects; Plasmodium falciparum/enzymology; Plasmodium falciparum/growth & development; Purinones/metabolism; Substrate Specificity
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HPRT	involved_in	GO:0046040: IMP metabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HPRT	enables	GO:0052657: guanine phosphoribosyltransferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:HPRT	involved_in	GO:0046038: GMP catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HPRT	involved_in	GO:0043103: hypoxanthine salvage	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:HPRT	enables	GO:0004422: hypoxanthine phosphoribosyltransferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:HPRT	involved_in	GO:0006178: guanine salvage	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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