Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2

Youngchang Kim, Jacek Wower, and colleagues explore the sequence specificity, metal ion dependence and catalytic mechanism of the Nsp15 endoribonuclease NendoU from SARS-CoV-2. The authors also solve five new crystal structures of the enzyme in complex with 5’UMP, 3’UMP, 5’cGpU, uridine 2′,3′-vanadate (transition state analog) and Tipiracil (uracil mimic), and demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme’s active site.