15-Jan-2021 - Max-Planck-Institut für biophysikalische Chemie

Why remdesivir does not fully stop the coronavirus

Remdesivir is the first drug against Covid-19 to be conditionally approved in Europe and the United States. The drug is designed to suppress the rapid replication of the SARS-CoV-2 virus in human cells by blocking the viral copying machine, called RNA polymerase. Researchers at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen and the University of Würzburg have now elucidated how remdesivir interferes with the viral polymerase during copying and why it does not inhibit it completely. Their results explain why the drug has a rather weak effect. (Nature Communications, January 12, 2021)

“After complicated studies, we come to a simple conclusion,” Max Planck Director Patrick Cramer says. “Remdesivir does interfere with the polymerase while doing its work, but only after some delay. And the drug does not fully stop the enzyme.” 

At the pandemic’s beginning, Cramer’s team at the MPI for Biophysical Chemistry had elucidated how the coronavirus duplicates its RNA genome. For the pathogen this is a colossal task as its genome comprises around 30,000 RNA building blocks, making it particularly long. To elucidate remdesivir’s mechanism of action, Cramer’s team collaborated with Claudia Höbartner’s group. The latter produced special RNA molecules for the structural and functional studies. “Remdesivir’s structure resembles that of RNA building blocks,” explains Höbartner, a professor of chemistry at the University of Würzburg. The polymerase is thereby misled and integrates the substance into the growing RNA chain.

Pausing instead of blocking

After remdesivir had been incorporated into the viral genome, the researchers examined the polymerase-RNA complexes using biochemical methods and cryo-electron microscopy. They discovered that the copying process pauses precisely when three more building blocks have been added after remdesivir was incorporated into the RNA chain. “The polymerase does not allow the installation of a fourth one. This pausing is caused by only two atoms in the structure of remdesivir that get hooked at a specific site on the polymerase. However, remdesivir does not fully block RNA production. Often, the polymerase continues its work after correcting the error,” explains Goran Kokic, a research associate in Cramer’s lab, who together with Hauke Hillen, Dimitry Tegunov, Christian Dienemann, and Florian Seitz, had conducted the crucial experiments. They all are first authors of the publication about this work recently published in the scientific magazine Nature Communications.

Understanding how remdesivir works opens up new opportunities for scientists to tackle the virus. “Now that we know how remdesivir inhibits the corona polymerase, we can work on improving the substance and its effect. In addition, we want to search for new compounds that stop the viral copying machine,” Max Planck Director Cramer says. “The vaccinations now underway are essential to bring the pandemic under control. But we also need to develop effective drugs that mitigate Covid-19 disease progression in the event of infection.”

Facts, background information, dossiers
  • Covid-19
  • Remdesivir
  • SARS-CoV-2
More about MPI für biophysikalische Chemie
  • News

    Molecular mechanisms of corona drug candidate Molnupiravir unraveled

    The United States recently secured 1.7 million doses of a compound that could help to treat Covid-19 patients. In preliminary studies, Molnupiravir reduced the transmission of the SARS-CoV-2 coronavirus. Researchers at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen an ... more

    Highly potent and stable nanobodies stop SARS-CoV-2

    A team of researchers has developed mini-antibodies that efficiently eliminate the SARS-CoV-2 coronavirus and its dangerous new variants. The so-called nanobodies bind and neutralize the virus up to 1000 times better than previously developed mini-antibodies. In addition, the researchers we ... more

    Errors at the start of life

    Only one in three fertilizations leads to a successful pregnancy. Many embryos fail to progress beyond early development. Cell biologists at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen (Germany), together with researchers at the Institute of Farm Animal Genetics in ... more

More about Uni Würzburg
  • News

    How Poxviruses Multiply

    Poxviruses have found a unique way of translating their genes into proteins in the infected organism. For the first time, scientists of the University of Würzburg's Biocenter have been able to gain atomic-level insights into the functioning of the molecular machinery involved in the process ... more

    Hobit Turns Immune Cells Into Killers

    Against infections, tumours and inflammations, immune cells are locally positioned as rapid reaction forces in the organs of the body. On site, they specialise and take on various tasks. When pathogens invade the human body, a rapid response is required. At the forefront of the immune respo ... more

    New Coating for Plastics to Fight Bacteria off

    The start-up Flux Polymers, which has its roots at the University of Würzburg, offers a simple and easy solution to keep plastic surfaces free of bacteria. Recently, it has found an investor and can now start its operational business. In clinics and medical practices, it is crucial to work ... more