Collect. Czech. Chem. Commun. 2010, 75, 1249-1257
Published online 2010-11-23 08:48:56

Inhibition of human purine nucleoside phosphorylase by tenofovir phosphate congeners

Ivan Votruba*, Jana Trýznová, Petra Břehová, Eva Tloušťová, Květoslava Horská, Jindřich Fanfrlík, Ondřej Přenosil and Antonín Holý

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Gilead Sciences & IOCB Research Centre, Centre for New Antivirals and Antineoplastics (IOCB), Center for Biomolecules and Complex Molecular Systems, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic


The structure-activity study on the phosphates of phosphonomethoxypropyl derivatives of purine bases interacting with human purine nucleoside phosphorylase has shown that the most efficient inhibitors of the enzyme are (R)- and (S)-PMPGp with Ki ~ 1.9 × 10–8 and/or 2.2 × 10–8 mol/l. The kinetic experiments have proven, with the exception of both enantiomers of PMP-8-BrDAPp, strictly competitive character of inhibition for all ANP monophosphates tested. Bromine derivatives exhibited uncompetitive and mixed type of inhibition as well. These results were confirmed by docking studies. The substitution of purine moiety with the bromine at the position 8 lead to an allosteric binding of these compounds toward the enzyme.

Keywords: Enzyme inhibitors; Enzyme kinetics; Phosphonates; Purine nucleoside phosphorylase; Phosphates of acyclic nucleoside phosphonates; Tenofovir phosphate congeners.

References: 15 live references.