PT  - JOURNAL ARTICLE
AU  - Youngchang Kim
AU  - Jacek Wower
AU  - Natalia Maltseva
AU  - Changsoo Chang
AU  - Robert Jedrzejczak
AU  - Mateusz Wilamowski
AU  - Soowon Kang
AU  - Vlad Nicolaescu
AU  - Glenn Randall
AU  - Karolina Michalska
AU  - Andrzej Joachimiak
TI  - Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2
AID  - 10.1101/2020.06.26.173872
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.26.173872
4099  - http://biorxiv.org/content/early/2020/06/28/2020.06.26.173872.short
4100  - http://biorxiv.org/content/early/2020/06/28/2020.06.26.173872.full
AB  - SARS-CoV-2 Nsp15 is a uridylate-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family. It degrades the polyuridine extensions in (−) sense strand of viral RNA and some non-translated RNA on (+) sense strand. This activity seems to be responsible for the interference with the innate immune response and evasion of host pattern recognition. Nsp15 is highly conserved in coronaviruses suggesting that its activity is important for virus replication. Here we report first structures with bound nucleotides and show that SARS-CoV-2 Nsp15 specifically recognizes U in a pattern previously predicted for EndoU. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. Inhibitors of Nsp15 have been reported but not actively pursued into therapeutics. The current COVID-19 pandemic brought to attention the repurposing of existing drugs and the rapid identification of new antiviral compounds. Tipiracil is an FDA approved drug that is used with trifluridine in the treatment of colorectal cancer. 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.Competing Interest StatementThe authors have declared no competing interest.