Drug Used To Treat Bipolar Disorder and Hearing Loss Stops Coronavirus from Replicating In Host Cells

Concerned by the rapid progress of the pandemic in early February, a team of researchers at the University of Chicago’s Pritzker School of Molecular Engineering (Chicago, IL, USA) decided to use their molecular modeling expertise to help find a treatment against the disease. At the same time, other groups around the world also began to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus. The researchers first focused on finding a weakness in the virus to target. They chose its main protease, Mpro which is a key coronavirus enzyme that plays a central role in its life cycle and facilitates the virus’ ability to transcribe its RNA and replicate its genome within the host cell.

A pharmaceutical drug that has shown promise as a weapon against Mpro is Ebselen, a chemical compound with anti-viral, anti-inflammatory, anti-oxidative, bactericidal, and cell-protective properties. Ebselen is used to treat multiple diseases, including bipolar disorders and hearing loss, and several clinical trials have proven its safety for use in humans. The researchers set out to develop detailed models of the enzyme and the drug. Using those models and sophisticated supercomputer simulations, they discovered that the small Ebselen molecule is able to decrease Mpro’s activity in two different ways.

“In addition to binding at the catalytic site of the enzyme, Ebselen also binds strongly to a distant site, which interferes with the enzyme’s catalytic function by relying on a mechanism in which information is carried from one region of a large molecule to another region far away from it through subtle structural reorganizations,” said Prof. Juan de Pablo, the Liew Family Professor of Molecular Engineering, who led the team of researchers.

The finding is particularly important as it helped explain Ebselen’s potential efficacy as a repurposed drug and revealed a new vulnerability in the virus that was previously not known and that could be use useful in developing new therapeutic strategies against COVID-19. The research team’s discovery of two binding sites looks promising for Ebselen to be a new drug lead for the design and development of new Mpro inhibitors and COVID-19 treatment.

“The main protease is one of many proteins in the virus that could be targeted with existing, repurposed drugs, and there are thousands of compounds to be considered,” de Pablo said. “We are systematically investigating each of the proteins involved in the virus function and investigating their vulnerabilities and their responses to a wide range of drugs.”

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