Preexisting drugs show promise in fight against COVID-19

First released in late 2019 in Wuhan City, China, the SARS-CoV-2 virus continues to cause illness and death worldwide. Researchers and scientists have been looking for multiple solutions to treat COVID-19, including re-application of approved pharmaceutical drugs. This research points to very promising treatment options.

A team of researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago used state-of-the-art computer simulations to identify a pre-existing drug that could track a solution to this global pandemic.

Their findings appear in the paper, “Molecular Characterization of Ebselen Binding Activity to SARS-CoV-2 Main 4 Protease,” which was published August 14 in the journal Science Advances.

Mpro Versus Ebselen

In early February, driven by the rapid progress of the pandemic, Professor Juan de Pablo and his students are using their expertise in molecular models to help find a cure for the disease. They were not the only ones. Other groups around the world began using supercomputers to quickly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus.

“Because of the large number of connections considered in high throughput screens, those calculations need to involve a number of simplifications, and the results then need to be evaluated with experiments and more sophisticated calculations,” Pablo explained.

Researchers first focused on finding a weakness in the virus to target. She chose the main protease: Mpro. Mpro is a major coronavirus enzyme that plays a central role in the life cycle of the virus. It enables the virus’ ability to transcribe its RNA and replicate its genome within the host cell.

A pharmaceutical medicine that shows promise as a weapon against Mpro is Ebselen. Ebselen is a chemical compound with anti-viral, anti-inflammatory, anti-oxidative, bactericidal, and self-protective properties. Ebselen is used to treat multiple ailments, including bipolar disorder and hearing loss. In combination with silver, Ebselen treats five clinically difficult-to-manage antibiotic-resistant Gram-negative bacteria. Several clinical studies have proven their safety for use in humans.

How it works

de Pablo and his students set out to develop detailed models of the enzyme and the medicine. Using these models and sober supercomputer simulations, they discovered that the small Ebselen molecule is capable of reducing the Mpro’s activity in two different ways.

“In addition to binding to the catalytic side of the enzyme, Ebselen also binds strongly to a remote side, which interferes with the catalytic function of the enzyme by relying on a mechanism in which information is carried out from one region of a large molecule. to another region away from it through subtle structural reorganizations, “says de Pablo.

This finding was particularly important because it helped explain the potential efficacy of Ebselen as a repurposed drug, and it revealed a new vulnerability in the virus that was previously unknown and that could be useful in developing new therapeutic strategies. against COVID-19.

By working round the clock, the team completed their work in just over two months and submitted their manuscript to public research archives in April for others to consider.

Drug development potential

The discovery of the research team of two binding sites seems to promise Ebselen a new medicine guide for the design and development of new Mpro inhibitors and COVID-19 treatment. Motivated by their findings, Pablo and his student are quick to point out that much work remains to be done.

“The main protease is one of many proteins in the virus that can be targeted to existing, reimbursed drugs, and there are thousands of compounds that need to be considered,” says Pablo. “We systematically examine each of the proteins involved in virus function and examine their vulnerability and their responses to a wide range of drugs.”

de Pablo and his team will soon release a comprehensive study of the RBD / ACE2 complex from the virus and another drug that promises to interfere with the binding of the virus to cells.