Cat coronavirus drug shows promise for treatment of COVID-19

Researchers at the University of Alberta have identified viral inhibitors that they say are strong candidates for the treatment of coronavirus disease 2019 (COVID-19).

Joanne Lemieux and colleagues say the dipeptide-based protease inhibitor, GC376, and its analog, GC373, should be fast-forwarded for testing in clinical trials of COVID-19.  The research is published on the preprint server bioRxiv*.

“They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats),” writes the team. “The work here lays the framework for their use in human trials for the treatment of COVID-19.”

The urgent need for antivirals

The virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - the virus strain that causes COVID-19 - has meant the number of confirmed cases has now reached more than 3.5 million, a number that is still rapidly growing.

Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (blue) infected with SARS-COV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (blue) infected with SARS-COV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

Antiviral agents that can be used to treat acute infection are urgently needed, especially given that it is expected to take at least a year before a vaccine becomes available.

The main protease (Mpro) is a prominent drug target

Once inside host cells, coronaviruses use the cell machinery to produce viral polyproteins, which are then cleaved by proteases to generate further proteins that are required for viral replication.

The main protease (Mpro) in SARS-CoV-2 is a viable and prominent drug target for the development of an antiviral therapy due to its essential role in cleaving the polyproteins.

Researchers have already developed various types of inhibitors of coronavirus Mpro, one of which has been used to cure cats with feline infectious peritonitis (FIP), a fatal infection caused by coronavirus.

The challenge the researchers faced

However, coronavirus Mpro is a cysteine protease, and “inhibition of cysteine proteases by thiol-reactive species is often untenable for human drugs unless the inhibitor is reversible,” explain Lemieux and team.

“In this regard, the reversible reaction of thiols with aldehyde inhibitors to make hemithioacetals presents a unique opportunity for effective cysteine protease inhibition, as they can potentially bind more effectively in the active site of their target protein than with other thiols.”

In previous studies, the team had developed peptide-based inhibitors, some of which they used to target the main protease of the Feline Coronavirus FCoV9.

The team says, “the bisulphite adduct GC376, which converts readily to peptide aldehyde GC373, was well tolerated and able to reverse the infection in cats. This, along with other studies that included ferret and mink coronavirus Mpro, demonstrated the broad specificity of this protease inhibitor.”

Given the effectiveness of these agents in cats, the team decided to test whether they inhibit SARS-CoV-2 Mpro and SARS-CoV Mpro in a reversible manner and could potentially be used as an antiviral therapy for humans.

In vitro studies revealed that both viral strains were successfully inhibited by GC373 and GC376, at nanomolar concentrations.

“NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal,” writes the team.

To test the agents’ ability to inhibit SARS-CoV-2, the team performed plaque reduction assays on infected cells in the presence and absence of GC373  or GC376 at increasing concentrations over the course of 48 hours.

To check for cytotoxicity, cellular production of ATP in the presence of the inhibitors was measured over the course of 48 hours.

The inhibitors were both effective and non-toxic

The results showed that both GC373 and GC376 were strong inhibitors of SARS-CoV-2 and had a therapeutic index of more than 200.

“These protease inhibitors are soluble, non-toxic, and bind reversibly,” writes the team.

The researchers also point out that “water-soluble aldehyde bisulphite adducts are readily made, reversibly from the parent aldehyde under physiological conditions, and can be ideal prodrugs for cysteine protease inhibition.”

The team says it is clear that these drugs should soon be tested in human trials of COVID-19, especially since it will probably take more than a year to develop a vaccine due to the challenges the virus is likely to present.

In the meantime, “it is likely that several very potent drugs will be required to treat SARS-CoV-2 and to prevent the evolution of resistance they may need to be used in combination,” note the researchers.

“We believe that GC373 and GC376 are candidate antivirals that should be accelerated into clinical trials for COVID-19,” they conclude.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally has a Bachelor's Degree in Biomedical Sciences (B.Sc.). She is a specialist in reviewing and summarising the latest findings across all areas of medicine covered in major, high-impact, world-leading international medical journals, international press conferences and bulletins from governmental agencies and regulatory bodies. At News-Medical, Sally generates daily news features, life science articles and interview coverage.

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Comments

  1. Pat We Pat We United States says:

    GC373 drug has been developed as a broad-spectrum antiviral agent against Picoranavirus, Calicivirus, and Coronavirus 3CL proteases and later expanded to Faline Coronavirus by a group of researchers in the USA. If these Canadian researchers do not have patent rights to GC37, it will be problematic in the future. If someone visits the google scholar pages of the authors of the current work, it is clear that they have done nothing related to viral proteases except for small mechanistic work before this. Here is the link to the patent which covers the original work by the US researchers. patents.google.com/patent/WO2013049382A2/en. Probably, this might lead to a legal battle in the near future.

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