id	author	title	date	pages	extension	mime	words	sentences	flesch	summary	cache	txt
cord-335443-iv2gs3kg	Kim, Youngchang	Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2	2020-06-28		.txt	text/plain	5464	333	57	Here, we combine crystallography, biochemical and whole cell assays, and show that this compound inhibits SARS-CoV-2 Nsp15 and interacts with the uridine binding pocket of the enzyme's active site, providing basis for the uracil scaffold-based drug development. For SARS-CoV it was reported that Nsp15 cleaves highly conserved non-translated RNA on (+) sense strand showing that both RNA sequence and structure are important for cleavage 6, 7 . The enzyme cleaves efficiently eicosamer 5'GAACU¯CAU¯GGACCU¯U¯GGCAG3' at all four uridine sites (Fig. 1) , as well as synthetic EndoU substrate ( 5′-6-FAM-dArU¯dAdA -6-TAMRA-3′ ) 8 in the presence of Mn 2+ and the reaction rate increases with metal ion concentration. SARS-CoV-2 Nsp15 protein was crystallized with 5'UMP, 3'UMP, 5'GpU and Tipiracil using methods described previously 8 and the structures were determined at 1.82 Å, 1.85 Å, 1.97 Å and 1.85 Å, respectively. In the crystal structure of Nsp15/5'GpU, the dinucleoside monophosphate binds to the active site with uracil interacting with Tyr343 and Ser294 (Fig. 4B ), as seen in the Nsp15/5'UMP complex.	./cache/cord-335443-iv2gs3kg.txt	./txt/cord-335443-iv2gs3kg.txt