Failing forward: How a drug that was meant to treat Ebola could be the right fit for COVID-19

Dr. Matthias Götte

In May 2016, the World Health Organization (WHO) published a special report about preventing epidemics [ PDF (12.5 MB) - external link ], which included a list of priority pathogens suspected of posing the greatest risk for severe outbreaks. For Dr. Matthias Götte, a virologist at the University of Alberta, this felt like a call to action.

Dr. Götte previously studied HIV and hepatitis C, but he decided to change his lab’s entire approach in 2017 in order to focus solely on the WHO’s list of pathogens. Specifically, the team studies the polymerases (enzymes) that each virus uses to build copies of itself. Such studies are crucial for antiviral drug development, as a better understanding of each virus-specific polymerase can reveal new ways to interfere with that virus’s ability to replicate—and if the replication can be stopped, then so can the infection.

A number of antiviral drugs have been developed in recent years, including some that target the polymerase as the keystone for blocking viral replication. One of those drugs, known as remdesivir, was initially tested against the Ebola virus in 2014. Although it did not perform well enough in clinical trials to be deemed an effective treatment for Ebola infection, remdesivir has since shown promise against coronaviruses, even though they are from a different virus family than Ebola.

While there was understandable excitement in the scientific community about this potential weapon that could be kept in the arsenal in the event of a coronavirus outbreak—the SARS virus from the 2003 crisis and Middle East respiratory syndrome (MERS) were both on the WHO’s list of risky pathogens, after all—there were no published studies about how the drug worked against them. This mystery intrigued Dr. Götte, who believes that understanding the “mechanism of action” for a drug is crucial for determining when that particular weapon will work.

Last summer, long before the COVID-19 pandemic was on the horizon, Dr. Götte and his team decided to study the MERS polymerase and then closely examine the effect of remdesivir on it. In February 2020, the team published a landmark paper that demonstrated how the drug mimics a key building block that the polymerase would normally use to construct additional copies of the virus. Essentially, it’s a fake-out: to the polymerase, the drug looks so much like this building block that it incorporates remdesivir into the new viral strand. But the drug doesn’t act like the crucial ingredient the polymerase was trying to use, so the new strand quickly becomes a dud and viral replication is stopped. This was what the drug developers originally hoped would happen with cases of Ebola infection, and while Dr. Götte notes that the mechanism of action for MERS is similar to the one envisioned for Ebola, the drug proved to be much more potent against MERS.

Dr. Götte and his team quickly turned their attention to SARS-CoV-2, the virus that causes COVID-19 disease, which is in the same virus family as MERS. In mid-April, they published another paper demonstrating that, much like with their MERS study, remdesivir is quite good at halting viral replication. The buzz resulting from the paper, along with the large body of other preclinical data, has led to a lot of speculation that the drug could be the treatment we need in the fight against COVID-19—but the next step involves taking the drug out of the lab and putting it to use in human clinical trials.

“We have to be patient,” says Dr. Götte, who is optimistic about the preliminary results but is quick to emphasize the need to make medical decisions based on sound scientific evidence. “Currently, the evidence justifies the move to clinical trials. But we can only answer the question of whether or not it is a good treatment once those trials are complete.”

In the meantime, Dr. Götte is pleased to see that research into potential treatments has already branched out to include different drug targets and tactics. “This is a new pathogen, so it’s vital that we start broadly, get as much data as possible, and then move the most promising treatments into clinical trials,” he explains. “This polymerase is a logical target, but there could be many more. We can’t afford to focus on only one.”

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