The novel coronavirus SARS-CoV-2 still remains a huge puzzle to scientists around the world. The only thing that is certain is that the pathogens reproduce at breakneck speed in human cells after an infection. This happens when the virus duplicates its genetic material. This is made up of one long RNA strand and it uses a kind of viral ‘photocopier’ to reproduce, otherwise known as a polymerase.
Researchers led by Patrick Cramer from the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, have now taken a major step forward in the study of the virus. They have succeeded in decoding the physical structure of the corona polymerase. The scientists explain that on the basis of this information they are now able to further examine how antiviral substances work. Such as Remdesivir, which blocks polymerase. On top of that, new drug possibilities can also be explored.
“In light of the current pandemic, we were keen to help,” says Cramer. “We have extensive experience in the study of polymerases.” The most surprising thing was that the structure of the coronavirus ‘photocopier’ was different from all other polymerase structures, according to research group member Hauke Hillen.
Although the corona polymerase binds to RNA in the same way as other types of viruses do, it has “another element that enables it to bind to RNA until it has copied the genetic material. This is particularly crucial in the case of the coronavirus as its genome consists of around 30,000 building blocks and is therefore extraordinarily long. “Copying that is truly a mammoth task.”
Optimizing older substances, finding new ones
Building on the knowledge of how the coronavirus polymerase is constructed atom by atom, the researchers now want to examine more closely how antiviral substances block the proliferation of coronaviruses. “A great deal of hope is pinned on Remdesivir, as this directly blocks the corona polymerase,” said Cramer. “The polymerase structure could potentially be able to optimize substances that already exist, such as Remdesivir, and enhance their effect. But we also want to look for new substances that are able to block the virus polymerase.”
Nevertheless, the team admits that the road to establishing the three-dimensional structure of the corona polymerase was rocky. “First, we had to reconstruct the polymerase from three purified proteins inside a test tube. It finally worked after a few tweaks,” Goran Kokic explains. “It was the only way that allowed us to study how it functioned.” The scientists had devised a special test in order to determine the activities of the polymerase.
However, examining the samples under an electron microscope at a magnification of over 100,000 times led to a dead end. “Although we took images around the clock for ten days and nights, we were unable to gain detailed insights into the structure,” Christian Dienemann recalls. He’s the team’s electron microscopy expert.
‘Strange’ sample leads to a breakthrough
However, one sample looked different, “a bit strange,” they thought. So, the researchers were inclined to dismiss it. But fortunately, they didn’t do that, says the group’s data processing expert Dimitry Tegunov. “This sample, of all things, provided us with the high-quality data we so desperately needed.”
As a next step, the Göttingen researchers now want to look for areas where the virus is vulnerable to attack. “We also have our sights set on the so-called helper molecules that alter the viral RNA in such a way that it cannot be decimated by the human immune system,” says Cramer. “And of course, as structural biologists, we hope to find more vulnerable areas in the virus that will open up new therapeutic strategies in the medium term.”
Cramer and his team have already published the results of their research on the Internet so that they can “immediately share them with the international research community seeing that things need to proceed especially fast now that we are in the middle of a pandemic.”
Title image: The polymerase of the novel coronavirus SARS-CoV-2 duplicates the genetic material (blue and red) of the pathogen. © Lucas Farnung, Christian Dienemann, Hauke Hillen / Max Planck Institute for Biophysical Chemistry
