Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: A new class of antimalarial therapeutics

0329059 - ÚOCHB 2010 RIV US eng J - Journal Article
Keough, D. T. - Hocková, Dana - Holý, Antonín - Naesens, L. - Skinner-Adams, T. S. - de Jersey, J. - Guddat, L. W.
Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: A new class of antimalarial therapeutics.
Journal of Medicinal Chemistry. Roč. 52, č. 14 (2009), s. 4391-4399. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT 1M0508; GA AV ČR 1QS400550501
Institutional research plan: CEZ:AV0Z40550506
Keywords : acyclic nucleoside phosphonates * phosphoribosyltransferase * enzyme inhibitors * Plasmodium falciparum
Subject RIV: CC - Organic Chemistry
Impact factor: 4.802, year: 2009

Plasmodium falciparum (Pf) relies on the purine salvage enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), for the synthesis of the mononucleotides. Acyclic nucleoside phosphonates (ANPs) are structural analogs of the mononucleotide product of the reaction and contain a purine base linked by different combinations of atoms to a phosphonate group. Ki values for 19 ANPs were determined for PfHGXPRT and human HGPRT. IC50 values for Pf grown in cell culture and the structures of human HGPRT in complex with three ANPs have been determined. These results provide a basis for the design of more potent and selective inhibitors as anti-malarial drugs with novel mode of action.
Permanent Link: http://hdl.handle.net/11104/0175194