Researchers at UBC’s Life Sciences Institute have identified a compound that shows early promise at halting infections from a spread of coronaviruses, including all variants of SARS-CoV-2 and the common cold.

The findings, published this week in Molecular Biomedicine, reveal a possible path toward antiviral treatments that might be used against many various pathogens.

Beyond COVID-19, there are a lot of several types of coronaviruses that could cause serious and sometimes fatal disease, and much more are prone to emerge in the long run.”

Dr. Yossef Av-Gay, infectious disease professor in UBC’s faculty of drugs and study’s senior writer

“We’re working toward treatments that will be broadly effective against all kinds of coronaviruses in order that we are able to reply to not only current health challenges, but in addition future pandemic threats. Identifying this compound and the pathway by which it really works to stop viruses is a vital step in that direction.”

Targeting the host, not the virus

The researchers credit the compound’s broad effectiveness to the unique way it really works. Quite than targeting the virus itself, the compound targets a human cellular process that coronaviruses use to copy.

Since viruses cannot reproduce on their very own, they depend on protein-synthesis pathways in host cells to create copies of themselves. Within the case of coronaviruses, they use a human enzyme called GSK3 beta that exists in all human cells.

“We found that coronaviruses hijack this human enzyme and use it to edit the protein that packs its genetic material,” says Dr. Tirosh Shapira, a postdoctoral fellow at UBC’s faculty of drugs and the study’s first writer. “This compound blocks GSK3 beta, which in turn, stops the virus from reproducing and maturing its proteins.”

The compound is a component of a broader family of experimental drugs referred to as GSK3 inhibitors. Because the late Nineties, scientists across academia and industry have been studying GSK3 inhibitors for his or her potential as treatments for plenty of diseases, including diabetes, Alzheimer’s and cancer.

“By targeting this cellular pathway, somewhat than the virus itself, we see broad activity against multiple pathogens. We’re also acting on a pathway that’s thus far proof against changes between variants and different coronaviruses,” says Dr. Shapira.

Future-proof treatments

To discover the compound, the research team screened a library of nearly 100 known GSK3 inhibitors, provided through a collaboration between UBC and Takeda Pharmaceutical Company in Japan. The compounds were tested in cell and tissue models infected with SARS-CoV-2 and the common cold virus.

The testing yielded multiple GSK3 inhibitors that showed a high level of effectiveness against the coronaviruses and low toxicity to human cells. The leading compound, identified as T-1686568, inhibited each SARS-CoV-2 and the common cold virus, the important criteria the authors utilized in the seek for broad-spectrum protection.

“While these are early days, it’s encouraging to see broad levels of effectiveness in tissue models,” says Dr. Shapira. “Because these compounds require a few years of testing and regulatory approval before they’ll potentially reach patients, we must be serious about long-term applications and the way this might apply broadly to future viruses and variants.”

The research was conducted at UBC FINDER, a level-3 biocontainment facility at UBC where researchers are working with highly infectious pathogens with an aim to develop future treatments.

“We’re not only fighting SARS-CoV-2, we’re looking ahead at what’s next,” says Dr. Shapira. “We’re focused on identifying future-proof treatments for variants and viruses that emerge down the road and depend on the identical cellular mechanisms to grow and infect.”

This research was supported by the TB Veterans Association, Genome British Columbia and the BC Lung Foundation.

Source:

University of British Columbia

Journal reference:

Shapira, T., et al. (2022) Inhibition of glycogen synthase kinase-3-beta (GSK3β) blocks nucleocapsid phosphorylation and SARS-CoV-2 replication. Molecular Biomedicine. doi.org/10.1186/s43556-022-00111-1.