An existing drug can disrupt the replication of coronaviruses

In early 2020, Eric Pringle and Brett Duguay spent most of their time in the microbiology lab on the seventh floor of the Dal's Tupper Building
.
Virologists are busy testing potential antiviral drugs for the common cold coronavirus and are seeing promising results
.

Both are postdoctoral fellows, working with Dr.
Craig McCormick, who is working on an approved drug that is already being used to treat other conditions
such as cancer and irritable bowel syndrome.
Their lab recently completed a separate study showing that the drug 6-thioguanine (6-TG) is surprisingly effective
at inhibiting influenza virus replication in the lab.

However, just as they were wrapping up this work, the World Health Organization declared COVID-19 a pandemic, triggering widespread lockdowns, laboratory closures, and some research disruptions
at institutions around the globe.

Some researchers studying the highly contagious and potentially deadly SARS-CoV-2 and other coronaviruses are excluded
.

"That's when we decided, 'We need to test this antiviral drug
we have against the flu on the coronavirus,'" Dr.
Duguay said in the dining room of the bright, busy lab.
So, we just got our hands on common cold coronaviruses (like OC43 and 229E) and we immediately tested 6-TG and it worked
immediately.
”

An "amazing result"

Like scientists around the world, they are trying to understand whether changing the use of existing drugs can be a safe and effective treatment for COVID-19
.
They would love to learn more about how coronaviruses interact with human host cells and where the dependencies lie, which may help determine where their weaknesses lie
.

Eventually, they discovered a novel effect or mechanism
of action of 6-TG.
In cell culture experiments, they found that the drug could inhibit replication of human coronaviruses, including SARS-CoV-2
.
It does this by interfering with the development of the virus's signature spike protein, which is necessary to
penetrate host cells and trigger infection.
Without them, viruses like SARS-CoV-2 cannot interact or spread
with host cells.

"One of the main outcomes of treating with this drug is that it inhibits the ability of the virus to make large amounts of spike proteins and merge them into new daughter viruses or juveniles, so the resulting juveniles do not have spikes and therefore cannot cause infection," said
Dr.
McCormick, a virologist in the Department of Microbiology and Immunology at the Dahl College.
"It's an amazing result
.
"

Dr.
Pringle explained that the spikes are glycosylated, meaning they are covered
in sugar.
These sugars help the virus evade the immune system by protecting the
spike away from antibodies.
We found that the antiviral 6-TG inhibits proper glycosylation, so the spike is not sugar-coated and does not work properly
.
”

Inhibits viruses

The researchers outlined their findings in a recent paper that they used the common cold coronavirus, and their colleagues at Saskatchewan and the University of Calgary are evaluating the effects
of 6-TG on SARS-CoV-2.
They measured the amount of
virus produced by cells infected by the virus and cells treated with the drug.
The number of replicates in the treated cells is very low
.

"That's what you want antiviral drugs to do — you want it to suppress the amount of virus produced so that the virus spreads less effectively, fewer people get sick, fewer people get sick
," Dr.
Duguay said.

The team is working with Dr.
Sultan Darvesh, a medicinal chemist and neuroscientist at Dalhousie, to better understand how the drug works and how it can be improved to target SARS-CoV-2
more effectively.
He is conducting computational studies to see how drugs interact
with proteins within cells.
The question is which protein in the host cell the drug works
.

Dr Darvesh said: "It could be like finding a needle
in a haystack.
We wanted to know which of these proteins was responsible for getting the virus into the cell, and once we found this protein, we could use the same calculations to see if we could make a better drug
than 6-TG.
I am very optimistic about
this drug.
”

The researchers stress that they do not encourage people to take 6-TG, and to date there is no evidence that people taking 6-TG for other reasons have any benefit
in treating COVID-19.
The discovery is an important first step in a long process that could take years to generate treatments
for future coronavirus outbreaks.

Dr McCormick said: "Antiviral drugs have a real role
to play in the viruses of the future.
I'm excited that we're illuminating a new field, which could be a new branch of this type of research, and we are providing evidence that this group of human proteins is a good target and plays an important role
in viral replication.
" ”