Donnelly Centre Investigators Win Emergency Funding to Identify Antivirals for COVID-19

Mar 6, 2020
Jovana Drinjakovic

Three researchers sitting around a table discussing scienceProfessor Sachdev Sidhu (centre), with former postdoctoral fellow Wei Zhang (left), who developed the pipeline for antiviral protein engineering and research associate Jacky Chung (right) who will spearhead the efforts to identify potential therapeutics for COVID-19.

Donnelly Centre researchers have received a funding boost to identify new antivirals that can combat the 2019 Novel Coronavirus outbreak (COVID-19). Led by Sachdev Sidhu, a professor of molecular genetics in the Donnelly Centre, the team will apply their protein engineering technology to identify promising therapeutics.

“We have diverse expertise on our team from across U of T and the University of Manitoba, which is renowned for its virology research, and we have already demonstrated that we can engineer proteins that inhibit MERS, a related coronavirus,” says Sidhu. “We will now expand on this work to design therapeutics for COVID-19.”

The team have received almost CAD900,000 over two years from the federal government from a rapid funding competition announced on February 10 to address the COVID-19 outbreak. Patty Hajdu, federal Health Minister said in Montreal today that the government invested close to $27M across the country to support research that could mitigate the outbreak and its negative impact on people.

Sidhu is collaborating with Roman Melnyk, a medicinal chemist and Senior Scientist at the Hospital for Sick Children, and Brian Mark, a structural virologist and Professor at the University of Manitoba. In a 2016 proof of principle study with Marjolein Kikkert, a virologist at Leiden University in the Netherlands, they applied a protein engineering pipeline developed by Sidhu’s team to create proteins that inhibit a related coronavirus which caused the Middle East Respiratory Syndrome (MERS) outbreak in 2012. Wei Zhang, then a postdoc in Sidhu’s lab and now Assistant Professor at the University of Guelph, received a national innovation award for this research.

Read more about this story in the Toronto Star.

The researchers now plan to use the same strategy to battle the coronavirus behind the global health scare.

Since the outbreak began in China in late 2019, the virus has spread to all the continents except Antarctica, with more than 100,000 confirmed cases and 3300 deaths, according to the latest figures from the World Health Organization. And while researchers around the world are racing to develop a vaccine, that is only a part of the solution, Sidhu said.

“Even if a vaccine becomes available, not everyone is going to get vaccinated,” says Sidhu. “We see that with the flu—the vaccination rates are far from 100 per cent.” Should the virus become endemic and end up circulating in the population like the flu, medicines that stop the virus from replicating in an already infected person will be as important as vaccines, which prevent infection, said Sidhu.

Jacky Chung, a research associate in the Sidhu lab will spearhead the project by first engineering the proteins that can inhibit the virus. The team will then search for small molecules that behave in the same way since they are easier to develop into therapeutics than proteins.

“It's important to get the therapeutic inside the cells, which is where the virus replicates,” says Chung. “And small molecules can get into cells much more readily than proteins, which are much larger.”

At the heart of the approach lies a protein called ubiquitin, named for being present in all plant and animal cells. Ubiquitin is an essential part of the cellular machinery which the virus hijacks for its own benefit. Upon infection, the virus releases proteins that interfere with human ubiquitin and allow it to bypass the host’s defense system and spread in the body.

To block the virus, the researchers will create synthetic ubiquitin variants (UbV) that thwart rather than aid its ability to replicate. By analyzing the molecular structures of different UbVs bound to the viral protein, they will gain clues into the kinds of small molecules that are most likely to be effective against the virus.

Sidhu thinks that within two years they will have candidate molecules that could be developed into therapeutics. “We know there are literally armies of medicinal chemists and various companies that could then optimize the molecule into a drug that can be given to humans,” says Sidhu who was previously at pharma giant Genentech and has founded six startups since joining U of T.

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