Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human UMP-CMP kinase |
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Authors: | Topalis Dimitri Kumamoto Hiroki Alexandre Julie A C Dugué Laurence Pochet Sylvie Berteina-Raboin Sabine Agrofoglio Luigi A Deville-Bonne Dominique |
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Affiliation: | Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, CNRS-Université Paris 6, 4 place Jussieu, F-75005 Paris, France. |
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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. |
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