Drug meant for Ebola may also work against coronaviruses

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A group of University of Alberta researchers who have discovered why the drug remdesivir is effective in treating the coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) expect it might also be effective for treating patients infected with the new COVID-19 strain. “Even if you know a drug works, it can be a red flag if you don’t know how it works,” said virologist Matthias Götte. “It is reassuring if you know exactly how it works against the target.
“We know the drug works against different coronaviruses, like MERS and SARS, and we know the novel coronavirus is very similar to SARS. So, I would say I’m cautiously optimistic that the results our team found with remdesivir and MERS will be similar with COVID-19.”

Until now, there has not been a published explanation of why remdesivir may work against coronaviruses, said Götte, who added his study is an important step in answering that question.

Developed by Gilead Sciences as a response to the 2014 West African Ebola virus epidemic, remdesivir was first used on a patient with the novel coronavirus earlier this year in the US. The patient was given the drug on the seventh day of illness, and showed marked improvement the following day, with symptoms eventually disappearing altogether. And at a recent press conference in Beijing, the assistant director-general of the World Health Organisation, Bruce Alyward, said remdesivir is the only drug available that may have real efficacy against COVID-19.

“What our study showed was that remdesivir essentially mimics one of the natural building blocks for RNA synthesis necessary for genome replication of the virus. Enzymes within the virus are synthesising the viral RNA genome with these building blocks, but they mix up the bits they need with the drug. Once the drug is incorporated into the growing RNA chain, the virus can no longer replicate,” explained Götte.

He said the next step is to wait for results from ongoing clinical trials with remdesivir, which are expected by the end of April. Even then, that won’t be the end of the story, he cautioned.

“It’s likely we’ll need more than one drug to properly fight emerging diseases like COVID-19, as we have with HIV and hepatitis C virus infections,” Götte said. “Ideally, we will have a couple of drugs because certain strains could be resistant to certain treatments.”

Götte’s study was supported by grants from the Canadian Institutes of Health Research and the Alberta Ministry of Economic Development, Trade and Tourism through the Major Innovation Fund Programme and Antimicrobial Resistance – One Health Consortium.

Abstract
Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including SARS-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogues.
Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i+3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3’–5’ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

Authors
Calvin J Gordon, Egor P Tchesnokov, Joy Y. Feng, Danielle P Porter, Matthias Gotte

University of Alberta Faculty of Medicine & Dentistry material

Journal Biological Chemistry abstract

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