The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes.
Scientists at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, have now determined the 3-D structure of the corona polymerase. They found that the structure of the coronavirus polymerase is special—it differs from other structures that we have been investigating so far.
Max Planck Director Cramer said, “In view of the current pandemic we wanted to help. We have extensive experience in studying polymerases. It was, therefore, obvious to the scientists what project to choose.”
“This makes it now possible to investigate how antiviral drugs such as remdesivir—which blocks the polymerase—work, and to search for new inhibitory substances.”
Scientists found that the coronavirus polymerase binds to the RNA as other types of viruses. Although, this polymerase contains an additional element with which it binds the RNA until it has copied the genetic material.
This is important for the coronavirus as its genome consists of around 30,000 building blocks and is therefore particularly long, making copying a significant challenge.
With this study, scientists hope to understand better and combat the pathogen. Their next step will be investigating how antiviral substances block the proliferation of coronaviruses.
Patrick Cramer, at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, said, “Many hopes rest on remdesivir, which directly blocks the polymerase. With the structure at hand, it might be possible to optimize existing substances such as remdesivir and to improve their effectiveness. But we also want to search for new substances that can stop the virus polymerase.”
Lucas Farnung, who will soon take up a professorship at Harvard University in the United States, said, “We wanted to immediately share our findings with the international scientific community to speed things up, now that we are in the middle of the pandemic.”
Goran Kokic said, “The path to the three-dimensional structure of the corona polymerase was rocky. First, we had to reconstitute the polymerase from three purified proteins. After some optimization, it was finally functional in the test tube.”
“Only then we were able to study how it works. To do so, the scientist had quickly established a special test to determine the activity of the polymerase.”
Christian Dienemann, an expert in electron microscopy, said, “We examined the samples in the electron microscope with a magnification of more than 100,000-fold—and at first disappointment set in: Although we took pictures around the clock for ten days and nights, we were unable to gain detailed insights into the structure.”
Dimitry Tegunov, the group’s data processing expert who also programmed the software to process large volumes of image data in a short time, said, “However, one sample looked different, somehow strange. Our first thought was to discard it. Fortunately, we did not: This sample, overall, provided us with the high-quality data we needed.”
Cramer said, “The determination of the polymerase structure will not be the last contribution of the Göttingen researchers to tackling the pandemic: We are planning to take a look at the helper factors that change the viral RNA in such a way that the human immune system cannot degrade it. And of course, as structural biologists, we hope to find further targets in the virus that might open up new therapeutic strategies in the medium term.”
- Hauke S. Hillen, Structure of replicating SARS-CoV-2 polymerase. DOI: 10.1101/2020.04.27.063180