How does a virus multiply

How does the coronavirus multiply its genetic makeup?

In order to multiply, the SARS-CoV-2 virus has to reproduce its genetic material, which consists of a long strand of RNA. The polymerase takes on this task. With the deciphering of the spatial structure, it is now possible to research how antiviral substances that block the polymerase work. One of them is remdesivir, the bearer of hope. In addition, new drug candidates can be searched for.

Extensive experience studying polymerases

“In the face of the current pandemic, we wanted to help,” says Max Planck Director Cramer. “We have extensive experience in studying polymerases.” The research topic was therefore obvious to the scientists. “The most surprising thing for us was that the structure of the coronavirus copier was out of line because it differs from other polymerase structures,” explains Hauke ​​Hillen. The corona polymerase binds to the RNA in the same way as it is known from other types of viruses. But this polymerase has another element with which it clings to the RNA until it has copied the genetic material. This is especially important for the coronavirus, because its genome consists of around 30,000 components and is therefore particularly long, copying a real mammoth task, according to the scientists.

Understand in detail how antivirals work

Knowing how the coronavirus polymerase is structured atom by atom opens up new possibilities to better understand and fight the pathogen. In the next step, Cramer's research team wants to investigate in detail how antiviral substances block the multiplication of coronaviruses. “Much hopes rest on remdesivir, which blocks the corona polymerase directly. The polymerase structure could make it possible to optimize existing substances such as Remdesivir and improve their effectiveness. But we also want to look for new substances that can stop the virus polymerase, ”said Cramer.

The Göttingen researchers have already published their results in a manuscript on the Internet. "We wanted to share our findings with the international research community straight away, because now that we are in the middle of the pandemic, we have to move particularly quickly," reports Lucas Farnung, who will shortly be moving to a professorship at Harvard University in the United States .

The corona copier enlarged 100,000 times

The way to the three-dimensional structure of the corona polymerase was rocky. “First we had to recreate the polymerase from three purified proteins in a test tube. After a few optimizations, it was finally functional, ”explains Goran Kokic. “This was the only way we could study how it works.” To this end, the scientist quickly established a special test to determine the activity of the polymerase.

Electron microscope images

The team then examined the samples in an electron microscope at over 100,000x magnification - and initially disappointment spread: "Although we took pictures around the clock for ten days and nights, we were unable to gain detailed insights into the structure," recalls Christian Dienemann, an expert in electron microscopy. “However, one sample looked different, somehow strange. Our first thought was to discard them. Fortunately, we didn't do that: of all things, this sample provided us with the high-quality data that we absolutely needed, ”explains Dimitry Tegunov, the group's data processing expert, who also programmed the software to quickly process large amounts of image data.

Helper factors in sight

The decoding of the polymerase structure should not be the last contribution of the Göttingen researchers to overcoming the pandemic: "We also have the so-called helper factors in our sights, which modify the virus RNA in such a way that it cannot be broken down by the human immune system", so Cramer. "And of course we, as structural biologists, hope to find further points of attack in the virus that will open up new therapeutic strategies in the medium term."

 

 

Source: idw / Max Planck Institute for Biophysical Chemistry