Drug strategies to fight COVID-19 move beyond guesses

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Doctors are exploring how to attack COVID-19 with antiviral treatments repurposed from HIV and Ebola.

COVID-19 is often mild. But it continues to kill and hospitalize so many that physicians hope repurposing existing antivirals could improve survival and reduce the time people are seriously ill.

No treatments for COVID-19 have been approved for use in Canada outside of clinical trials.

Doctors and scientists are exploring three main ways to mitigate SARS-CoV2 infection, the virus that causes COVID-19, so more patients recover. The strategies are based on how the virus enters our cells and makes copies of itself a processknown as replication.

The experimental antiviral medication remdesivir could be the most high profile example. Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, said in late April that remdesivir shortened recovery time from 15 days without specific treatment, compared with 11 days on average with the drug.

The hope is if remdesivir succeeds in shortening recovery from COVID-19, it will reduce the burden on health-care systems the goal of broader efforts to flatten the curve.

Viral engine stalls

Matthias Gotte, a professor of medical microbiology and immunology at the University of Alberta, discovered why remedesvir seems to be such a potent antiviral.

He compared the way the virus copies itself to the engine of a car.

"The engine needs gas," he said, in reference to how COVID-19 infection transmits. With remdesivir, the engine gets diesel and stalls. "The virus stops to replicate and stops to propagate."

Alan Bernstein, a trained virologist and president and CEO of the non-profit CIFAR, a Canadian-based, global research organization that brings together top researchers to address important questions, previously led a major HIV vaccine effort.

"That's the attraction of repurposing," Bernstein said of remdesivirand other antiviral trials. "You already have a drug;you know it's safe at a certain dose."

Canadian doctors await key details such as if the drug in fact improves survival, when it works best, if it will be available in clinical trials in this county and what it will cost.

The three main antiviral strategies doctors and scientists are exploring are:

• Stop the virus' raison d'etre of copying or replicating its RNA genetic material. These drugs, called polymerase inhibitors, include remdesivir, which has shown antiviral activity against this coronavirus.

• Stop the virus from properly building the proteins it needs by blocking the snipping tool it uses to do it. These drugs are called protease inhibitors and include lopinavir and ritonavir, used to treat HIV.

• Prevent the virus from entering our cells in the first place.

Using the car analogy,Gotte likened the viral copying enzyme, called polymerase, to a vehicle'sengine.

Bernstein said remdesivir throws a monkey wrench into the virus's ability to incorporate the RNA building blocks it needs to copy itself.

Remdesivir was intended to treat Ebola, but other treatments worked better for that viral infection.

Dr. Ilan Schwartz is an infectious disease physician at the University of Alberta who is not involved in clinical trials of potential antivirals to fight COVID-19. He's following their progress.

"We're cautiously optimistic," Schwartz said. "We're certainly not talking about something that is going to have a benefit for everyone."

Remdesivir and other potential treatments should not be prescribed outside of a clinical trial, he said. More needs to be known about the benefits and risks.

Since remdesivir is given to patients by intravenous infusion, doctors say it's unlikely to gain widespread use outside of hospitals. Favipiravir, another polymerase inhibitor, that's given orally, is expected to start testingin a Phase 2 clinical trial in long-term care homes in Ontario this month.

Dr. Ken Milne, chief of staff at South Huron Hospital Association in Exeter, Ont., co-hosted a town hall on potential antivirals for the Canadian Association of Emergency Physicians.

Milne said he's still looking for high-quality evidence that remdesivir and other potential antivirals to fight COVID-19 offer benefits that are important to patients, such as survival without disability.

"I'm skeptical because the evidence that's been published so far doesn't support its routine use," said Milne, creator of the Skeptics Guide to Emergency Medicine, a podcast and blog geared to those involved in patient care.

Milne said in HIV, antivirals are taken long term to improve quality of life. In contrast, COVID-19 is a short-term illness and most recover. That means the bar for safety and effectiveness differ.

AI meets drug design

Two HIV antivirals called lopinavir and ritonavir are protease inhibitors that are used in combination with other anti-HIV treatments to suppress the virus.

When HIV or SARS-CoV-2 enter a human cell, the virus hijacks the cell's machinery into making more copies of the virus by co-opting certain polyproteins or chains of proteins.

WATCH |Antiviral drug remdesivir shows promise as COVID-19 treatment:

Antiviral drug remdesivir shows promise as COVID-19 treatment

4 years ago

Duration 1:59

The antiviral drug remdesivir is showing promise as a COVID-19 treatment in early U.S. clinical trials, though other research hasnt seen as much success.

Bernstein, thevirologist, said to think of polyproteins as two or three sentences fused together without a period between them.

"The protease comes along and snips at the period or snips the polyprotein into three or four smaller proteins. A protease inhibitor blocks the protein that does that snipping," Bernstein said.

Eric Arts, a professor of microbiology and immunology at Western University in London, Ont., said scientists are better off at this stage of the COVID-19 epidemic than at the start of the HIV epidemic, before the advent of protease inhibitors.

"The field of virology and drug development has advanced so much," said Arts, who holds a Canada Research Chair in HIV. "It's day and night. When we were trying to find a drug for HIV 30 years ago, it was a guessing game."

Patience will pay off

With SARS CoV2, researchers know the structure of the viral proteins down to basically the atom level, Arts said. This knowledge also includes the key protein on the surface of our cells that the virus uses to enter, called the ACE2 receptor.

"We can design molecules that would disrupt that interaction," Arts said. "Or, and this gets really kind of sci-fi, we can take existing drugs, knowing their structures and then do what we call a computer-aided, AI kind of study and see how those existing drugs may dock and block that interaction."

Pharmaceutical companies have compound libraries of these molecules that scientists, aided by AI, can sift through for candidates that look like they may work effectively against SARS CoV2.

"It's a very effective way to find something that works," Arts said, compared with the conventional drug screening approach of conducting tests in the lab followed by animal models and then a decade of clinical trials in humans.

Che Colpitts, an assistant professor in biomedical and molecular sciences at Queen's University, is working to find new antiviral strategies against RNA viruses. She uses models that resemble the deadly pathogens, including SARS-CoV-2 and another coronavirus disease, MERS.

Colpitts previously looked at how natural compounds produced by plants and fungi to protect themselves could interfere with viral attachment.

"Everybody is definitely jumping on," to research SARS-CoV-2, she said. "It's just a really exciting time."

Colpitts and physicians who've treated COVID-19 say a critical factor for prescribing antivirals is to give them to patients before too much damage has set in.

Until effective vaccines exist, people need to continue physical distancing, hand hygiene, cough etiquette and to stay home when sick, public health officials, physicians and researchers say.

"With treatment or something that could be effective and good screening, we can control this disease pretty effectively until we have a vaccine," Arts said. "It's just we have to be a little more patient for a little while longer and we will have relief."

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