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Explained: How remdesivir tricks coronavirus

Remdesivir is designed to obstruct the stage of replication, when the virus creates copies of itself, followed endlessly by the copies creating copies of themselves.

Written by Kabir Firaque | New Delhi |
Updated: May 9, 2020 4:30:12 pm
Explained: How remdesivir tricks coronavirus Rubber stoppers are placed onto filled vials of the investigational drug remdesivir at a Gilead manufacturing site in the United States. (Gilead Sciences via AP)

In all the debate over the efficacy of remdesivir in treating COVID-19 patients, what has been clear is the way the drug acts — or is meant to act — against the novel coronavirus SARS-CoV2. Remdesivir is designed to obstruct the stage of replication, when the virus creates copies of itself, followed endlessly by the copies creating copies of themselves.

Research last month concluded that remdesivir indeed works this way, and a new paper last week described the exact mechanism of interaction between the virus and the drug.

How does replication take place?

Once the virus enters the human cell, it releases its genetic material, which is then copied using the body’s existing mechanism. At every stage of infection, various human proteins, virus proteins, and their interactions come into play. At the replication stage, the key viral protein at play is an enzyme called RdRp (an enzyme is a kind of protein that speeds up chemical reactions within a cell).

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Also read | US allows emergency use of remdesivir for Covid-19 patients

It is RdRp that makes the copies, by processing components of the RNA of the virus. University of Alberta researchers called it the “engine” of the virus in a paper last week, in which they described the action of remdesivir against this “engine”. Again, researchers at the Max Planck Institute of Biophysical Chemistry in Germany described the same enzyme as the “copy machine” of the virus when they imaged the architecture of this “machine” in 3D.

In scientific literature, such an enzyme is called a polymerase (the p is RdRp stands for polymerase) or a replicase. In any case, this is the enzyme that is targeted by remdesivir.

And how exactly does remdesivir target this enzyme?

In order to replicate, the copy machine processes raw material from the virus RNA, broken down by another enzyme with that specific function. When a patient is given remdesivir — the inhibitor — it mimics some of this material, and gets incorporated in the replication site. With remdesivir replacing the material it needs, the virus fails to replicate further.

“These coronavirus polymerases are sloppy and they get fooled, so the inhibitor gets incorporated many times and the virus can no longer replicate,” University of Alberta microbiologist and immunologist Matthias Götte said in a statement.

How far has this action been established?

This is what the University of Alberta researchers reported in the Journal of Biological Chemistry. Using insect cells, they expressed RdRp complexes of SARS-CoV (the coronavirus responsible for SARS) and SARS-CoV2 (which causes COVID-19). They found that an active compound in remdesivir inhibits the copy machines of both viruses with the same potency and mechanism of action.

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Previously, the same team had found similar results for remdesivir action against the coronavirus that causes MERS. The drug itself was designed to act against the Ebola virus, which is not a coronavirus.

As far as SARS-CoV2 is concerned, a paper by Chinese researchers last week has added to the emerging knowledge about the action of remdesivir.

What are these new findings?

Researchers from various institutions under the Chinese Academy of Sciences have imaged the high-resolution structure of the SARS-CoV-2 replicase complex, with remdesivir bound to it. They have published their findings in Science.

The structure shows where the virus’s RNA template enters the copy machine, where remdesivir is incorporated, and where the process of replication is terminated. The Chinese researchers too used insect cells.

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