By Vanessa Virgo

U of G researchers are on the hunt for chemical inhibitors that could be used to treat COVID-19 by halting viral progression in infected patients.  

Dr. Wei Zhang, a professor in the College of Biological Science, says previous researchers found small molecule inhibitors that prevented viral progression of the SARS-CoV and MERS-CoV viruses. 

Following the earlier model, he and his team at the Zhang Lab [1] looked for a molecule that could inhibit papain-like protease (PLpro). This enzyme cuts viral polyproteins of SARS-CoV-2 and interferes with modification of human proteins, allowing the virus to evade the body’s immune surveillance and spread throughout the body.  

“Our research with small molecule inhibitors will allow us to develop specific and effective therapeutics for treating SARS-CoV-2 and will aid in any efforts to combat future pandemics,” says Zhang. 

He screened a chemical library of 3,000 compounds approved by the U.S. Food and Drug Administration to treat various diseases. To determine binding efficacy, the researchers used molecular dynamics, which analyzes the movements of molecules using a computer simulation. This produced 30 small molecules with binding potential.  

After obtaining all 30 chemicals from commercial distributors, researchers conducted enzymatic activity assays to determine whether the molecules could inhibit PLpro.  

The assays produced seven molecules with mild inhibitory properties. The most efficient molecule, Sennidin-A, was five times less effective than GRL-0617, a small molecule known to be an effective inhibitor that has yet to undergo clinical trials.  

“This research will help to refine our search for a small molecule that can effectively bind to and inhibit PLpro,” says Zhang.  

Chemical inhibitors are preferred over protein-based inhibitors developed earlier by other researchers for MERS-CoV PLpro, says Zhang. The former inhibitors are more readily available and have better pharmacological properties than small proteins, making it easier to gain approval for clinical trials. 

To find a chemical inhibitor effective at treating COVID, his team will continue screening a larger, non-FDA-approved chemical library. Zhang aims to find a small molecule that mimics the workings of the newly developed SARS-CoV2 PLpro protein-based inhibitor. 

This research project was funded by the Chandler Foundation and the University of Guelph’s COVID-19 Research Development and Catalyst Fund.