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COVID-19: Why Remdesivir has only limited effect against the virus

Effect of remdesivir deciphered

In the search for effective drugs against the coronavirus SARS-CoV-2, attention fell early on the Ebola drug Remdesivir and in July this was the first drug to be approved in the EU against COVID-19. However, the drug only provides limited help, and a recent study has now revealed why Remdesivir cannot completely stop the virus from replicating.

Researchers from the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen and the University of Würzburg have studied the effect of Remdesivir against the coronavirus and deciphered how the drug affects the reproduction of the virus and why this cannot be stopped completely. The results of the study were published in the journal “Nature Communications”.

Virus multiplication is inhibited

As the first drug against COVID-19, Remdesivir was approved in Europe in July under certain conditions. “The active ingredient is designed to suppress the rapid multiplication of the SARS-CoV-2 pathogen in human cells by stopping the viral copying machine, called RNA polymerase,” the Max Planck Institute (MPI) for Biophysical Chemistry explains in a press release on the current study results.

In the study, the researchers were able to show how Remdesivir interferes with the viral polymerase during copying, but it also became clear that it does not completely inhibit the replication of the virus. This explains why the drug has a rather weak effect, the MPI reports.

“After complicated studies, we come to a simple conclusion: remdesivir does interfere with the polymerase in its work, but only after some delay. And the drug does not stop the enzyme completely,” summarizes Max Planck Director Patrick Cramer.

Incorporation into the RNA chain

“Remdesivir resembles RNA building blocks in its structure,” explains Professor Claudia Höbartner from the University of Würzburg. This misleads the polymerase of the virus and incorporates the substance into the growing RNA chain. The researchers used biochemical methods and cryo-electron microscopy to investigate what happens next. They found that the copying process pauses precisely when the RNA chain has lengthened by three additional RNA building blocks after the incorporation of remdesivir.

“The polymerase no longer allows a fourth building block. This is due to only two atoms in the structure of remdesivir, which get hooked at a certain point in the polymerase,” reports Goran Kokic of the MPI. However, remdesivir does not completely block RNA production, he said. “Often, the polymerase continues to work after error correction,” Kokic said.

Hope for better drugs

Understanding about remdesivir’s mechanism of action against SARS-CoV-2 also opens up new opportunities in the fight against the virus, according to the researchers. “Now that we know how remdesivir inhibits corona polymerase, we can work to improve the compound and its efficacy,” Cramer points out. While the vaccinations that have been started are essential to bring the pandemic under control, “we must also continue to develop effective drugs that mitigate the course of COVID-19 in the event of infection,” the MPI director concludes.

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