Mechanism clarified: Remdesivir is disappointingly weak in Covid-19. Researchers may now have found the reason for this. Accordingly, the active ingredient stops the synthesis of new strands of viral RNA, as their analyzes show. However, the virus can bypass this blockage and then continues to multiply only with a slight delay. Knowing about these mechanisms could help to develop new, more effective inhibitors.
Remdesivir is so far the only antiviral drug approved for the treatment of corona infection. The active ingredient is supposed to inhibit the reproduction of SARS-CoV-2 by disrupting the synthesis of new RNA strands. Remdesivir acts as a so-called nucleotide analog: Because its structure is similar to the RNA building blocks, the viral polymerase enzyme mistakenly incorporates it into the genome of the new virus copies. That blocks the completion of the viral RNA – so the plan.
Goran Kokic from the Max Planck Institute for Biophysical Chemistry in Göttingen and his colleagues have now explained how Remdesivir does this in practice and how the virus reacts to it. With the help of various biochemical methods and cryo-electron microscopy, they followed step by step what happens after the incorporation of remdesivir into the RNA of the coronavirus.
It turned out that the growth of the new RNA chain stops when three more RNA building blocks are attached after the remdesivir. “ The polymerase no longer allows a fourth building block,” explains Kokic. “This is due to only two atoms in the structure of Remdesivir that get caught at a certain point on the polymerase.” The protruding part of the molecule prevents the polymerase from rearranging the newly attached RNA building blocks in order to make space for further components.
“Remdesivir hinders the work of the polymerase, but only with some delay,” reports Kokic’s colleague Patrick Cramer.
Virus can clear the blockage
In addition, this blockade of RNA synthesis is usually not permanent. The coronavirus has enzymes that recognize copying errors in the freshly built RNA chains and cut out incorrect RNA bases. As the researchers observed, these exonucleases can also remove the remdesivir from the RNA chain. This also eliminates the copy blockage caused by the active ingredient.
This could explain why the antiviral in use on Covid 19 patients is less effective than initially hoped. “Remdesivir does not completely block RNA production. The polymerase often continues to work after an error has been corrected, ”explains Kokic. Virus replication then resumes after a delay.
Opportunity for improved active ingredients
According to the scientists, these findings could now help to develop more effective antiviral agents against SARS-CoV-2: “Now that we know how Remdesivir inhibits corona polymerase, we can work on improving the substance and its effects “Says Cramer. “In addition, we want to search for new substances that will stop the viral copying machine.”
The vaccinations that have now started are essential to bring the pandemic under control. But for people who are already infected, there is an urgent need for effective drugs that can alleviate the course of Covid-19. (Nature Communications, 2021; doi: 10.1038 / s41467-020-20542-0)
Source: Max Planck Institute for Biophysical Chemistry