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

SUMMARY

• 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.

FIGURE

ADVANTAGES

ADVANTAGES

• 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.

APPLICATIONS

• This technology has potential applications in COVID-19 treatment.

January 3, 2022

Proof of concept

Patent Issued

Licensing,Co-development

Natalia Maltseva

• PCT/US21/21913