Team uncovers new compounds to slow SARS-CoV-2 replication mechanism

A team of researchers at the University of Alberta has uncovered new antiviral agents that could lead to safer and more effective COVID-19 treatments than other current drugs under development.

In a recently published paper in the Journal of Medicinal Chemistry, the researchers identified novel protease inhibitor compounds that interfere with the SARS-CoV-2 virus’s ability to replicate itself, and also strongly inhibit other non-SARS coronaviruses. In a second paper in RSC Medicinal Chemistry, they also identified inhibitors that work through a different mechanism.

The researchers reported that both series of compounds demonstrate good selectivity — which indicates the ratio between efficacy and side-effects — and potential as a therapeutic treatment.

“We’ve made over 50 compounds and screened them for efficacy in both in vitro with recombinant protein, as well as in cell studies with live virus, and these compounds show very high specificity for the protease,” said Joanne Lemieux, principal investigator on the study, biochemistry professor in the Faculty of Medicine & Dentistry and director of the Membrane Protein Disease Research Group.

“Using X-ray crystallography and structural biology, as well as chemical design, the compounds were modified to have a better fit into the active site to make a more effective inhibitor, and cellular studies showed very low toxicity,” Lemieux said. “That combination indicates a very high selectivity index for our lead candidate.”

U of A research teams collaborate to expedite discoveries

Lemieux’s lab received funding from the Canadian Institutes of Health Research and Alberta Innovates. They worked with co-investigators Lorne Tyrrell, Distinguished University Professor of medical microbiology and immunology and founder of the Li Ka Shing Institute of Virology; James Nieman, head of chemistry for the Applied Virology Institute; Howard Young, professor of biochemistry; and John Vederas, University Professor of chemistry in the Faculty of Science.

“Our teams have been extremely productive together,” Lemieux said. “We’ve made very fast progress because we’re all here at the University of Alberta.”

(From left) Researchers Lorne Tyrrell, James Nieman and Joanne Lemieux combined their expertise with that of U of A colleagues Howard Young and John Vederas (not pictured) to identify inhibitor compounds that work against SARS-CoV-2 as well as other coronaviruses. (Photo: John Ulan)
(From left) Researchers Lorne Tyrrell, James Nieman and Joanne Lemieux combined their expertise with that of U of A colleagues Howard Young and John Vederas (not pictured) to identify inhibitor compounds that work against SARS-CoV-2 as well as other coronaviruses. “We’ve made very fast progress because we’re all here at the University of Alberta,” says Lemieux. (Photo: John Ulan)

Lemieux said the next step for the new compounds will be to look at the pharmacokinetics in mice, measuring how the drugs are absorbed, distributed, metabolized and excreted.

They will also test the compounds against variants of the SARS-CoV-2 virus that are proving more contagious and virulent.

“The protease cuts a very long polypeptide, and what we’re finding is that some of the variants have a protease that is more active and could potentially enhance the replication of the virus in itself,” Lemieux said. “We want to ensure that the drugs being developed will also work with variants of concern and variants of interest, including those identified here in Alberta.”

The goal is to develop a treatment that could be taken as a pill, rather than an intravenous drug that can only be given in hospital.

The teams also continue to test an enhanced version of a drug originally developed to treat a disease in cats that is caused by a coronavirus, which they hope will be more effective at a lower dose. The team’s first paper on the drug, published in Nature Communications, has been accessed online more than 58,000 times and cited more than 130 times, making it one of the most-accessed COVID-19 papers of 2020. Work on an improved form of the feline drug was recently published in the European Journal of Medicinal Chemistry.

“It’s an exciting time for antiviral drug development,” Lemieux said. “The main protease of SARS-CoV-2 is one of the top targets, but there is an urgent need to develop antivirals for other potentially threatening future endemic viruses as well.”

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