3'-N-alkylamino-3'-deoxy-ara-uridines: a new class of potential inhibitors of ribonuclease A and angiogenin

Abstract

In this study, we report the inhibition of ribonuclease A (RNase A) by certain aminonucleosides. This is the first such instance of the use of this group of compounds to investigate the inhibitory activity of this protein. The compounds synthesized have been tested for their ability to inhibit the ribonucleolytic activity of RNase A by an agarose gel-based assay. A tRNA precipitation assay and inhibition kinetic studies with cytidine 2',3'-cyclic monophosphate as the substrate have also been conducted for two of the compounds. Results indicate substantial inhibitory activity with inhibition association constants in the micromolar range. The experimental studies have been substantiated by docking of the aminonucleoside ligands to RNase A using AutoDock. We find that the ligands preferentially bind to the active site of the protein molecule with a favorable free energy of binding. The study has been extended to a member of the ribonuclease superfamily, angiogenin, which is a potent inducer of blood vessel formation. We show that the aminonucleosides act as potent inhibitors of angiogenin induced angiogenesis.