Drug Repurposing To Inhibit Nsp15 Endoribonuclease/NendU From SARS-CoV-2

Interests: Infectious Disease, Small Molecules

Published: January 3, 2022

Lead Inventor: Natalia Maltseva

There have been significant research efforts to develop various COVID-19 treatments. Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus i.e. SARS-CoV-2, which has spread rapidly throughout the world and was declared a global pandemic by WHO in March 2020.
Nsp15 is a nidoviral RNA uridylate-specific endoribonuclease (NendoU) carrying a C-terminal catalytic domain belonging to the EndoU family. Nsp15 enzyme is essential in coronavirus biology and there is a need for inhibiting Nsp15 activity to provide therapeutic interventions, particularly to treat diseases caused by nidoviruses that encode Nsp15.
The invention is a potential small molecule treatment for COVID-19 utilizing combination of an on-the-market drug (tipiracil) which is a candidate for a COVID-19 therapy and COVID-19 enzyme (NendoU).
Tipiracil targeting of NedoU was not previously known but it has been effective in colon cancer due to inhibition of thymidine phosphorylase which metabolizes trifluridine.
It may be possible to repurpose this drug against SARS CoV-2 virus with Nsp15 being the drug target as Nsp15 is one of essential non-structural proteins of SARS CoV-2 virus.

First of its kind small molecule repurposed drug-enzyme combination approach for COVID-19 treatment.
The on-the-market drug (tipiracil) has been utilized for colon cancer treatment previously and co-crystallization of the drug and NendoU provided information about critical touch points between drug and enzyme.
The developed assay confirmed active derivatives and allowed the broad expansion of known structure for broader applications.