Understanding exactly how antiviral drugs interact with viruses at a molecular level will be key to developing the broad-spectrum therapies needed to battle against the SARS-CoV-2 pandemic and get ready to fight the next one, according to a newly published paper in the The Journal of Biological Chemistry.
The paper reveals the inner workings of the drug remdesivir against different families of viruses. Remdesivir has been given to more than nine million COVID-19 patients worldwide, and is so far the only small-molecule antiviral drug that has Health Canada approval to treat the disease.
“The findings of studies such as this one help us understand the molecular basis of antiviral activity, and thus facilitate the development of oral antivirals with a broad spectrum of activity,” said lead author Matthias Götte, professor and chair of the Department of Medical Microbiology and Immunology at the University of Alberta.
Until now it was not understood why remdesivir works in lab tests against some viruses including coronaviruses, Ebola, hepatitis C and Nipah virus, but not against others such as influenza and Crimean-Congo hemorrhagic fever virus.
“We found that certain biochemical parameters are extremely important,” said Götte, noting that it all comes down to how well the drug tricks the polymerase, which is the replication engine of the virus and the target of remdesivir.
“Remdesivir is very well incorporated by the polymerase of SARS-CoV-2 and not so well by other viruses where it does not work,” he said, adding that once it is incorporated, the drug inhibits all viral polymerases tested in the study.
More than one drug needed
Now that the interactions between remdesivir and several other viruses are better understood, the next step will be to modify the compound to be better accepted by the polymerase of a broader range of other viruses.
“What we would like to have when the next pandemic strikes — and it's not a question of if, it's a question of when — what we need to have on the first day is a broad-spectrum antiviral agent,” Götte said.
Another key to successful antivirals is timing. Clinical trials have shown that remdesivir reduces the risk of hospitalization by 87 per cent when it is given early in the course of illness, but because it is currently only available intravenously, it’s sometimes given too late to have its full effect, Götte explained. The United States and Europe recently recommended remdesivir for early use in outpatients with mild to moderate disease, and Götte hopes Canada will follow suit. While vaccination remains the most important available tool against SARS-CoV-2, he said remdesivir continues to be effective against the Omicron variant and could play an important role in reducing the burden on our health system.
Götte said the new Pfizer oral antiviral drug that has just been approved by Health Canada appears to be as effective as remdesivir at preventing hospitalizations when given early. Another orally available antiviral drug, molnupiravir, has just been given FDA approval for use against COVID-19 in the United States, even though it appears to prevent only about 30 per cent of hospitalizations. It also shows activity against other viruses, including influenza.
For Götte, the more antiviral options we have available, the better. If a new virus strikes, it will take time to develop a vaccine, and treatments will be needed around the world while we wait. The ideal situation would be to treat patients with more than one antiviral at a time, much like the “cocktails” used for HIV and hepatitis C.
“When you combine antiviral drugs, it is more efficacious, more potent, and you reduce the likelihood of the virus developing resistance to any one drug,” he said.
Collaboration is key
Work will continue at the U of A to study, improve and design drugs that inhibit viral polymerases and other targets, using $55 million worth of new equipment and research funding recently awarded by the Government of Alberta.
“The grant really brings together at the University of Alberta different, yet related, expertise including immunologists, virologists, biochemists and chemists, to increase the probability of success in these very complicated and difficult endeavours,” Götte said.
Götte’s remdesivir research was funded by the Canadian Institutes of Health Research, Gilead Sciences, Inc. and the Alberta Ministry of Jobs, Economy and Innovation, and was carried out with help from graduate students Calvin Gordon and Hery Lee, research associate Egor Tchesnokov and scientists at Gilead.