Identification of small-molecule inhibitors of the XendoU endoribonucleases family

Abstract

The XendoU family of enzymes includes several proteins displaying high sequence homology. The members characterized so far are endoribonucleases sharing similar biochemical properties and a common architecture in their active sites. Despite their similarities, these proteins are involved in distinct RNA-processing pathways in different organisms. The amphibian XendoU participates in the biosynthesis of small nucleolar RNAs, the human PP11 is supposed to play specialized roles in placental tissue, and NendoU has critical function in coronavirus replication. Notably, XendoU family members have been implicated in human pathologies such as cancer and respiratory diseases: PP11 is aberrantly expressed in various tumors, while NendoU activity has been associated with respiratory infections by pathogenic coronaviruses. The present study is aimed at identifying small molecules that may selectively interfere with these enzymatic activities. Combining structure-based virtual screening and experimental approaches, we identified four molecules that specifically inhibited the catalytic activity of XendoU and PP11 in the low micromolar range. Moreover, docking experiments strongly suggested that these compounds might also bind to the active site of NendoU, thus impairing the catalytic activity essential for the coronavirus life cycle. The identified compounds, while allowing deep investigation of the molecular functions of this enzyme family, may also represent leads for the development of new therapeutic tools.