June 4, 2021

Screening Existing Compound Libraries for Potential Coronavirus Therapeutics

High-throughput biochemical assays targeting a vital viral protein identified one molecule out of more than 13,000 with promising antiviral activity against SARS-CoV-2

illustration of coronavirus particle and structure of nsp15 protein

High-throughput screening methodologies to search molecular libraries for antivirals active against the novel coronavirus, SARS-CoV-2, may also be useful to develop potent antivirals in future pandemics.

(Composite image by Timothy Holland | Pacific Northwest National Laboratory)

The Science                                

Vaccines for the novel coronavirus are becoming available around the world, but it will take time for a vaccination strategy to slow the spread of the virus. Therefore, medicines to treat COVID-19 are still needed. To speed the development of new antivirals, a multi-institutional team of scientists screened more than 13,000 compounds from existing drug libraries for the ability to inhibit a nonstructural protein of SARS-CoV-2 called nsp15. Three hits were confirmed as potent nsp15 inhibitors in vitro. Native mass spectrometry confirmed that one of those hits bound to nsp15. Cell-based assays confirmed the one hit possessed modest antiviral activity against SARS-CoV-2.

The Impact

The coronavirus nonstructural protein nsp15 is highly conserved among coronaviruses. It is also a key component for viral replication with no corresponding counterpart in host cells. These factors make it an intriguing candidate for drug development using two common approaches: high-throughput screening and structure-guided drug discovery. The screening methodologies described in this work to confirm, characterize, and validate molecules that inhibit a SARS-CoV-2 protein could also be useful to rapidly develop potent antivirals in future pandemics.


A multi-institutional team of scientists, including researchers from the University of Washington School of Medicine and the U.S Department of Energy’s Pacific Northwest National Laboratory, screened more than 13,000 compounds in existing libraries of drug and lead repurposing compound libraries for activity against nsp15 from SARS-CoV-2, the novel coronavirus that causes COVID-19. Their assays identified three hits as inhibiting nsp15 activity in vitro.

Native mass spectrometry capabilities at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy Office of Science user facility at Pacific Northwest National Laboratory, confirmed that one of those hits bound to nsp15. This candidate is a molecule called Exebryl-1, a ß-amyloid anti-aggregation molecule designed for Alzheimer’s disease therapy. Exebryl-1 did not have sufficient anti-viral activity in cell-based assays for immediate drug repurposing efforts. However, artificial intelligence-based lead optimization using the Exebryl-1 scaffold together with in silico molecular docking calculations onto the crystal structure of nsp15 are being used for medicinal chemistry optimization of this compound to improve its antiviral properties.


Mowei Zhou
Pacific Northwest National Laboratory

Neeraj Kumar
Pacific Northwest National Laboratory


Garry Buchko
Pacific Northwest National Laboratory

Wesley Van Voorhis
University of Washington School of Medicine


This project has been funded in whole or in part from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, and by the U.S. Department of Energy Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with the later funding provided by the Coronavirus CARES Act. Part of the research was conducted at the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by U.S. DOE Office of Science, Biological and Environmental Research program located at Pacific Northwest National Laboratory.