Synthesis, Structural Studies and Evaluation of Inhibitors of the 3CL Protease of SARS-CoV-2 as Potential Drugs for Treating Infection

Lemieux, Joanne M | $714,250

Alberta University of Alberta 2020 CIHR Operating Grant

The coronavirus, formally known as SARS-CoV-2, is viewed as a global health emergency since its 1st appearance in Dec 2019. Coronaviruses are spread through close contact from coughs & sneezes, but may also spread from animals, feces or contaminated surfaces. As of Feb 2020, > 44,730 people are infected in China and >1114 have died (97 in a single day). Seven cases have been reported in Canada. This disease, Covid-19, could become a pandemic unless appropriate measures or cures are found. In past work on a similar coronavirus, Severe Acute Respiratory Syndrome (SARS) virus prevalent in 2002-03, our group modified inhibitors for a protein it produces and requires, namely the 3CL protease. This protein is essential for replication and infectivity of that SARS virus. Genome sequencing of the current virus, SARS-CoV-2, demonstrates that it also has a 3CL protease that is nearly identical (96% the same). Of the 306 amino acid residues in the chain that makes the 3CL protease of the SARS-CoV-2 virus, only 12 are different and they are highly similar in properties. Recently, chemical compounds we previously made for the original SARS 3CL inhibition were slightly altered and one new derivative was shown to cure cats of feline infectious peritonitis (FIP), a natural mutant of feline enteric coronavirus (FECV). This infection is almost always fatal, but the key compound effected cures or significant remissions in all the cats. We propose to make the key compound and a series of its analogs by chemical synthesis. In addition, we propose to clone and express the 3CL protease (non-infectious) of the coronavirus SARS-CoV-2. We propose to assay all synthetic compounds as inhibitors of the 3CL protease, and to obtain X-ray crystal structures of the protease with these potential drugs to facilitate further inhibitor design. In a virology lab, compounds will be examined for their ability to kill the virus in infected cell lines.

With funding from the Government of Canada

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