Looking for new pyrimidine acyclic nucleotide analogues designed for phosphorylation by human UMP-CMP kinase.
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.
Topalis
Dimitri
D
Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, CNRS-Université Paris 6, 4 place Jussieu, F-75005 Paris, France.
Kumamoto
Hiroki
H
Alexandre
Julie A C
JA
Dugué
Laurence
L
Pochet
Sylvie
S
Berteina-Raboin
Sabine
S
Agrofoglio
Luigi A
LA
Deville-Bonne
Dominique
D
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry; D010766:Phosphorylation; D011742:Pyrimidine Nucleotides / Q000737:chemistry* / Q000302:isolation & purification*; D014753:Vinyl Compounds / Q000737:chemistry
D005456:Fluorescent Dyes; C527049:MABA-CDP; D063065:Organophosphonates; D011742:Pyrimidine Nucleotides; D014753:Vinyl Compounds; C433467:vinylphosphonic acid; D000244:Adenosine Diphosphate; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase