Since appearing in late 2019, the SARS-CoV-2 virus has caused sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. One such preexisting drug that offers promise as a possible treatment option is called Ebselen.
A team of researchers at the Pritzker School of Molecular Engineering at the University of Chicago used state-of-the-art computer simulations to explain how Ebselen may counteract the virus. Their findings, which could help provide new avenues to boost Ebselen’s effectiveness as well as suggest approaches for other drugs, appear in a paper published Aug. 14 in the journal Science Advances.
Mpro vs. Ebselen
Early in February, concerned by the rapid progress of the pandemic, Prof. Juan de Pablo and his group began to use their molecular modeling expertise to help find a treatment against the disease. They were not the only ones. Other groups around the world were beginning to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus.
“By virtue of the large number of compounds considered in high-throughput screens, those calculations must necessarily involve a number of simplifications, and the results must then be evaluated using experiments and more refined calculations,” explained de Pablo, the Liew Family Professor of Molecular Engineering.
Researchers first focused on finding a weakness in the virus to target. They chose Mpro, a key enzyme that plays a central role in the virus’s life cycle. It facilitates the virus’s ability to transcribe its RNA and replicate its genome within the host cell.
A pharmaceutical drug that shows promise as a weapon against Mpro is Ebselen. Ebselen, a chemical compound with anti-viral and anti-inflammatory properties, is already used to treat multiple diseases, including bipolar disorders and hearing loss. Clinical trials have evaluated its safety for use in humans.
How it works
de Pablo and his students 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 interfere with Mpro’s activity in two different ways.
Mpro works by cutting up specific pieces of virus so that it can replicate itself; Ebselen binds to not only one, but at least two sites, and prevents Mpro from working.
That finding was particularly important because it helped explain Ebselen’s potential efficacy as a repurposed drug, and it revealed a new vulnerability in the virus that was previously not known and that could be useful in developing new therapeutic strategies against COVID-19.
By working around the clock, the team completed their work in just over two months and submitted their manuscript to publicly accessible research archives in April for others to consider.
Drug development potential
The research team’s discovery of two binding sites looks promising for Ebselen as a drug candidate and, moving forward, for the design and development of new Mpro inhibitors and COVID-19 treatment. Though motivated by their findings, de Pablo and his student were quick to point out that much work is yet to be done.
“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 studying each of the proteins involved in the virus function and investigating their vulnerabilities and their responses to a wide range of drugs. It is also important to recognize that all of our predictions are made using models, and their validity must be assessed in experiments and clinical studies. That work will necessarily involve the contributions of many other research groups from around the world.”
de Pablo and his team will soon release a comprehensive study of a particular section of the virus called the RBD/ACE2 complex, and another drug that offers promise to interfere with the binding of the virus to cells.
The first author on the paper is Pritzker Molecular Engineering researcher Cintia A. Menéndez; other co-authors were Fabian Byléhn, Gustavo R. Perez-Lemus, and Walter Alvarado.
Citation: "Molecular characterization of Ebselen binding activity to SARS-CoV-2 main protease." Science Advances, Aug. 14, 2020.
Funding: Facilities, models, and algorithms used for this research are supported by the National Science Foundation, the Department of Energy, and the Department of Defense.
—Adapted from a story by Wendy Bedwell-Wilson first published to the Pritzker School of Molecular Engineering website.
—Prof. Jacqueline Stewart
