Antiviral Drug For Fatal Cat Disease Being Tested Against Coronavirus


 
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By Emma Betuel

"Since this drug has already been tested in cats, FDA approval may be faster."

Before humans were dealing with covid-19, our cats were succumbing to their own deadly coronavirus. A different coronavirus that causes the disease feline infectious peritonitis (FIP) kills 700,000 cats per year. After an infection is confirmed, death is almost certain.

Like the novel coronavirus in humans, there are no FDA-approved cures for FIP. However, new evidence is suggesting that the drugs that can fight one may help us contain the other.

A drug that combats the cat coronavirus has shown promise against SARS-CoV-2. In a study published last week, the drug stopped the coronavirus from replicating by targeting a key part of its machinery.

The study technically focuses on a drug called GC373 and a prodrug called GC376, which is GC373 with a compound added to make it soluble. Researchers found that both drugs inhibited SARS-CoV-2 in cell culture experiments.

Historically, GC376 has been tested in cats, where it has shown benefits. In a 2016 study, cats with FIP who got the drug recovered after 20 days (they would have died otherwise, the paper suggests). The manufacturer of GC376, the biopharmaceutical company ANVIVE, reports that the drug is in the "mid-stage" of being of approved as FIP treatment.

However, the drug has not been FDA-approved – even for cats. It hasn't been tested in humans against SARS-CoV-2 either.

Joanne Lemieux is a professor of biochemistry and the study's lead author. She says that because the drug has been tested in cats, it's more likely to move quickly through the testing process.

Repurposing a cat drug may sound outlandish, but scientists have been looking for drugs that already exist to treat coronavirus.

If they work, these drugs could reach patients far quicker than a drug no one has invented yet. This cat drug isn't far along the path, but Lemieux says that her group has partnered with ANVIVE to pursue FDA approval for the drug in humans, not just cats.

"For a drug to move forward in clinical trials, testing needs to be conducted in animals to determine safety and dosage. But this has already been completed," tells Lemieux. "Since this drug has already been tested in cats, FDA approval may be faster."

How does it work? – When scientists look to incapacitate SARS-CoV-2 they look for parts of the virus that they can interfere with. For instance, some researchers have targeted the spike protein, which the coronavirus uses to latch on to cells.

Rather than targeting the spike protein, this cat drug targets an enzyme that the coronavirus requires to release its genetic material into a cell, and start the dangerous process of replicating there.

The coronavirus contains genetic instructions to make one very long protein. That protein needs to get sliced in half before the virus can start replicating in the cell. An enzyme called Mpro does that slicing.

Without that slicing action, "infection cannot proceed," Lemieux says.

The coronavirus that causes feline infectious peritonitis also has a "main protease" that serves the same molecular scissor function. Past studies on cats, ferrets, and minks suggest that protease inhibitors (like GC376) can stop that scissoring from happening.

Lemieux and her collegues found that GC373 and GC376 can stop the scissoring function of Mpro and decrease the amount of virus present in cells. The effect was enough where they argue that: "Clearly, these drugs need to be advanced quickly into human trials."

Cat drugs and covid-19 – This is not the first time a drug used to treat cats with feline infectious peritonitis has showed promise against Covid-19. Another cat-oriented drug, called GS-441524, is essentially identical to remdesivir – the drug that currently has the FDA's emergency use authorization for use in hospitalized Covid-19 patients.

That drug is also not FDA-approved for humans and cats, though cat owners have been seeking it on the black market anyway. Should the FDA ever approve remdesivir for use outside of emergency situations, it could open the drug up to cat owners who have been seeking it to cure their pets of FIP — a strange side effect of the search for at Covid-19 drug.

Lemieux notes that the drugs in this study are also available on the black market as a cat medicine. But like GS-441524, it may now have two paths towards approval in two species. As scientists seek approval for the prodrug GC376 specifically against the coronavirus humans, it's possible cats could benefit too as the drug becomes a focus of renewed attention.

Whether it really helps treat or prevent Covid-19 can only be determined through clinical trials that pit the drug against Covid-19 in humans. Should it prove as effective as early-stage work suggests, it highlights just how important it is to care for the health of animals, as well as people.

Abstract: The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.



 
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