Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human UMP-CMP kinase.

Dimitri Topalis, Hiroki Kumamoto, Julie A C Alexandre, Laurence Dugué, Sylvie Pochet, Sabine Berteina-Raboin, Luigi A Agrofoglio, Dominique Deville-Bonne

Index: Nucleosides Nucleotides Nucleic Acids 26 , 1369-1373, (2007)

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Abstract

Human UMP-CMP kinase is involved in the phosphorylation of nucleic acid precursors and also in the activation of antiviral analogues including cidofovir, an acyclic phosphonate compound that mimicks dCMP and shows a broad antiviral spectrum. The binding of ligands to the enzyme was here investigated using a fluorescent probe and a competitive titration assay. At the acceptor site, the enzyme was found to accommodate any base, purine and pyrimidine, including thymidine. A method for screening analogues based on their affinity for the UMP binding site was developed. The affinities of uracil vinylphosphonate derivatives modified in the 5 position were found similar to (d)UMP and (d)CMP and improved when compared to cidofovir.