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PMID:19527031

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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

Significance

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


See also

References

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