Looking for New Pyrimidine Acyclic Nucleotide Analogues Designed for Phosphorylation by Human Ump-Cmp Kinase

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.

Keywords:

• Structure activity relationship
• acyclic nucleotide phosphonate
• UMP-CMP kinase
• cidofovir
• MABA-CDP

These studies were supported by a grant from Sanofi-Aventis France and Bayer Pharma as part of a multi-organism call for proposals.