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Designing therapeutics for the coronavirus - on all fronts

Guest post by Patrick Wu a Life Science Marketing Consultant based in Alberta.
As we enter the fourth month of physical distancing in Alberta, I’m sure many of us are eagerly waiting for the day that the COVID-19 pandemic comes to an end.
While researchers in Alberta are already working hard on a potential vaccine for SARS-CoV-2, many others are looking for antiviral drugs. Antivirals could help shorten hospitalization stays, increase our healthcare capacity, and buy us more time until a vaccine is developed.

So what’s in a virus?

Coronaviruses are RNA viruses and have some of the largest viral genomes known so far. The genome encodes some very important enzymes that are critical for its function.
You can see what they are in this figure (Image by Rohan Bir Singh, MD; Made with Biorender.com)
You probably already know about the characteristic spike protein - many articles talk about is as a strong candidate for vaccines. But the spike is not the only thing that researchers are looking at.

The polymerase

The replicase-helicase complex is also known as the RNA polymerase. Once the virus enters the cell, this important enzyme is responsible for making more copies of its genome.
Dr. Ken Ng and Dr. Chang-Chun Ling from the University of Calgary are studying the polymerase and are looking for molecules that could inhibit its activity.
According to Ng, the polymerase is unusual because most other polymerases (such as those in animals) need to use DNA in order to replicate RNA. SARS-CoV-2 does not.
“There isn’t really an equivalent of this enzyme in animals or plants,” says Ng.
Given this, it may be possible to design a drug that is specific to the virus while minimizing the side effects on human polymerases. He is working closely with Ling, a synthetic organic chemist whose lab is designing and testing new molecules to inhibit the polymerase. Their combined efforts could lead to some new drug candidates down the road.

The proteases

When the viral RNA enters the host cell, the ribosomes in the cell will use it to produce a polypeptide chain, which contains all the proteins in the virus. But the proteins can’t do anything until the chain is split into individual proteins. The papain-like protease (PLP) and 3CL-protease are the enzymes responsible for doing that.
A team of researchers at the University of Alberta, including Joanne Lemieux, John Vederas, James Nieman, and Lorne Tyrell, are targeting these proteases. Using what they know about feline coronavirus drugs, they are testing if the same drugs are able to inhibit the 3CL-protease in SARS-CoV-2. Early in vitro tests seem to suggest that they might.
“We saw less virus particles being made when the drug is present [in cell culture],” says Lemieux. “And the important thing is that [we see] little to no toxicity in the cells.”
If successful, this could reduce the rate in which the virus makes new particles.

The RNA itself

The coronavirus RNA is a flexible chain. It folds up on itself and creates complex structures, known as pseudoknots. Michael Woodside, a physicist at the University of Alberta, has been studying these pseudoknots for the past decade.
Pseudoknots can cause something called a frameshift. Normally, ribosomes read triplets of RNA bases as it assembles a protein. But pseudoknots can cause the ribosome to “slip” and change its reading frame, producing a new protein. It’s like a bicycle chain might slip gears.
That’s not always a bad thing; many organisms have genes in different reading frames. But for SARS-CoV-2, we can use this to our advantage.
“One of the gene products of the frameshift is actually the RNA polymerase,” says Woodside, “So if you knock down the expression of the polymerase, then the virus can’t replicate.”
His lab is using computational models to find molecules that can disrupt these pseudoknots, which would then disrupt gene expression. He hopes that this could be used as part of a combination therapy with other drugs to hit the coronavirus at multiple angles.
In the end, the combined efforts of all of this research will likely be the most effective way to stop the spread.
“No one single thing is usually quite strong enough,” Woodside remarks, “But with the right combination it can be much more effective.”

Designing therapeutics for the coronavirus - on all fronts

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