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

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Article in peer-reviewed journal

Nucleosides Nucleotides & Nucleic Acids 26, 10 (2007) 1369-73

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

Dimitri Topalis¹, Hiroki Kumamoto², Julie A C Alexandre¹, Laurence Dugué³, Sylvie Pochet³, Sabine Berteina-Raboin², Luigi A Agrofoglio², Dominique Deville-Bonne¹

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.

1:	Laboratoire d'Enzymologie Moléculaire et fonctionnelle

2:	ICOA - Institut de Chimie Organique et Analytique

3:	UCO - Chimie Organique


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