Researchers at UBC’s Institute of Life Sciences have identified a compound that shows early promise in stopping infections from a range of coronaviruses, including all variants of SARS-CoV-2 and the common cold.
The findings, published this week in Molecular Biomedicine, reveal a potential path toward antiviral treatments that could be used against many different pathogens.
Beyond COVID-19, there are many different types of coronaviruses that can cause serious and sometimes fatal illness, with even more likely to emerge in the future.”
Dr. Yossef Av-Gay, professor of infectious diseases at the UBC School of Medicine and lead author of the study
“We are working on treatments that can be broadly effective against all types of coronaviruses so that we can respond not only to current health challenges, but also to future pandemic threats. Identifying this compound and the pathway by which it works to stop the virus is an important step in that direction.”
Target the host, not the virus
The researchers attribute the broad effectiveness of the compound to the unique way it works. Instead of targeting the virus itself, the compound targets a human cellular process that coronaviruses use to replicate.
Since viruses cannot reproduce on their own, they rely on protein synthesis pathways in host cells to create copies of themselves. In 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 contains their genetic material,” says Dr. Tirosh Shapira, a postdoctoral fellow at the UBC School of Medicine and first author of the study. “This compound blocks GSK3 beta, which in turn prevents the virus from reproducing and maturing its proteins.”
The compound is part of a larger family of experimental drugs known as GSK3 inhibitors. Since the late 1990s, scientists from academia and industry have been studying GSK3 inhibitors for their potential as treatments for a number of diseases, including diabetes, Alzheimer’s, and cancer.
“By targeting this cellular pathway, rather than the virus itself, we see broad activity against multiple pathogens. We are also acting on a pathway that is so far immune to changes between variants and different coronaviruses,” says Dr. Shapira.
Future-proof treatments
To identify 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 tests yielded multiple GSK3 inhibitors that showed a high level of effectiveness against coronaviruses and low toxicity to human cells. The lead compound, identified as T-1686568, inhibited both SARS-CoV-2 and the common cold virus, the primary criteria the authors used in their search for broad-spectrum protection.
“While these are early days, it is encouraging to see broad levels of effectiveness in tissue models,” says Dr. Shapira. “Because these compounds require many years of testing and regulatory approval before they can potentially reach patients, we need to think about long-term applications and how this could broadly apply to future viruses and variants.”
The The research was carried out at UBC FINDER, a level 3 biocontainment facility at UBC where researchers are working with highly infectious pathogens with the goal of developing future treatments.
“We’re not just fighting SARS-CoV-2, we’re looking to the future,” says Dr. Shapira. “We are focused on identifying future-proof treatments for variants and viruses that emerge down the road and rely on the same cellular mechanisms to grow and infect.”
This research was supported by the Veterans Tuberculosis Association, British Columbia Genome, and the BC Lung Foundation.
Fountain:
University of British Columbia
Magazine reference:
Shapira, T., et al. (2022) Inhibition of glycogen synthase kinase-3-beta (GSK3β) blocks nucleocapsid phosphorylation and replication of SARS-CoV-2. Molecular Biomedicine. doi.org/10.1186/s43556-022-00111-1.
Source: news.google.com