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Inhibition of Hypoxanthine-Guanine Phosphoribosyltransferase by Acyclic Nucleoside Phosphonates: A New Class of Antimalarial Therapeutics
- Source :
- Journal of Medicinal Chemistry. 52:4391-4399
- Publication Year :
- 2009
- Publisher :
- American Chemical Society (ACS), 2009.
-
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.
- Subjects :
- Models, Molecular
Purine
Hypoxanthine Phosphoribosyltransferase
Erythrocytes
Purinones
Cell Survival
Stereochemistry
Plasmodium falciparum
Organophosphonates
Crystallography, X-Ray
Substrate Specificity
Antimalarials
Inhibitory Concentration 50
chemistry.chemical_compound
Catalytic Domain
Cell Line, Tumor
Drug Discovery
Animals
Humans
Nucleotide
Enzyme Inhibitors
Nucleotide salvage
chemistry.chemical_classification
biology
Chemistry
Active site
Nucleosides
Biochemistry
Hypoxanthine-guanine phosphoribosyltransferase
biology.protein
Nucleic acid
Molecular Medicine
Phosphoribosyltransferase
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....d3a1dadd5d4931af8a9313b318c6d2d9