After the 2003 outbreak of severe acute respiratory syndrome (SARS), researchers developed an antiviral drug that proved to be effective against feline coronavirus (FCoV), which sometimes leads to feline infectious peritonitis (FIP), an often fatal disease in cats. Now it appears that the antiviral drug, a dipeptide-based protease inhibitor, may benefit COVID-19 patients.
The new findings are being reported by scientists at the University of Alberta (U of A), one of whom was also involved in the earliest work on the antiviral drug. This scientist, John C. Vederas, PhD, professor of chemistry, like his U of A colleagues D. Lorne Tyrrell, MD, PhD, professor, department of medical microbiology & immunology and M. Joanne Lemieux, PhD, professor of structural biology, is a corresponding author of a paper (“Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication”) that appeared August 27 in Nature Communications.
Actually, the findings first appeared May 4 on BioRxIV, a research website. But the scientists could hardly be accused of letting the cat out of the bag. “There’s a rule with COVID research that all results need to be made public immediately,” said Lemieux, which is why the findings were posted before being published in a peer-reviewed journal.
She added that the article, which reflects the contributions of four U of A laboratories and the Stanford Synchrotron Radiation Lightsource, was accessed thousands of times as soon as it was posted. The scientists synthesized their antiviral compounds—a prodrug (GC376) and its parent (GC373)—and tested them against the SARS-CoV-2 virus in test tubes and in human cell lines. The scientists also studied crystal structures to determine how the drug binds with its protease target.
“In just two months, our results have shown that the drug is effective at inhibiting viral replication in cells with SARS-CoV-2,” Lemieux asserted. “This drug is very likely to work in humans, so we’re encouraged that it will be an effective antiviral treatment for COVID-19 patients.”
The U of A researchers are preparing to launch clinical trials of the drug. In the meantime, they will continue to test modifications of the drug. “We determined the three-dimensional shape of the protease with the drug in the active site pocket, showing the mechanism of inhibition,” she explained. “This will allow us to develop even more effective drugs.” She added, however, that the current drug shows enough antiviral action against SARS-CoV-2 to proceed immediately to clinical trials.
In their Nature Communications article, the scientists examined the use of the prodrug, GC376, and the parent drug, GC373, to test inhibition of the SARS-CoV-2 Mpro in vitro. By inhibiting Mpro, which plays an essential role in the cleavage of the virus polypeptide, GC376 and GC373 interferes with the virus’s ability to replicate, thus ending an infection.
“We demonstrate using recombinant SARS-CoV-2 Mpro that GC373 and GC376 are potent inhibitors in the nanomolar range,” the article’s authors detailed. “Crystal structures and NMR analysis of SARS-CoV-2 Mpro with GC373 and GC376 demonstrates the drug is covalently attached to Cys145 as a hemithioacetal and reveals residues important in inhibitor specificity. In cell culture, we show GC376 and GC373 block virus replication with no toxicity.”
The researchers have established a collaboration with Anivive Life Sciences, a veterinary medicine company that is developing the drug for cats, to produce the quality and quantity of drug needed for human clinical trials. Lemieux said it will likely be tested in Alberta in combination with other promising antivirals such as remdesivir, the first treatment approved for conditional use in some countries including the United States and Canada.
“Typically for a drug to go into clinical trials, it has to be confirmed in the lab and then tested in animal models,” Lemieux emphasized. “Because this drug has already been used to treat cats with coronavirus, and it’s effective with little to no toxicity, it’s already passed those stages, and this allows us to move forward.”