Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human ump-cmp kinase.

Dimitri Topalis (1) , Hiroki Kumamoto (2) , Julie a C Alexandre (1) , Laurence Dugué (3) , Sylvie Pochet (3) , Sabine Berteina-Raboin (2) , Luigi A Agrofoglio (2) , Dominique Deville-Bonne (1)

1 Enzymologie Moléculaire et Fonctionnelle
2 ICOA - Institut de Chimie Organique et Analytique
3 Chimie Organique

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.

Domaines: Microbiologie et Parasitologie

Dimitri Topalis, Hiroki Kumamoto, Julie a C Alexandre, Laurence Dugué, Sylvie Pochet, et al.. Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human ump-cmp kinase.. Nucleosides, Nucleotides and Nucleic Acids, 2007, 26 (10), pp.1369-73. ⟨10.1080/15257770701533982⟩. ⟨pasteur-00202298⟩