Sars-CoV-2
Using the X-ray light source BESSY II, researchers have decoded the three-dimensional structure of a main protein of the novel coronavirus. Manfred Weiss from the Helmholtz Center Berlin explains how this can speed up the search for a drug.
Mr. Weiss, Sars-Cov-2 is spreading faster and faster all over the world. Researchers are working flat out to develop an active ingredient against the novel corona virus. How can BESSY II help?
BESSY II is a synchrotron source at the Helmholtz-Zentrum Berlin that generates high-intensity X-ray light for research. Our modern instruments help to decode the 3D structure of proteins. We have been operating jet pipes for more than 15 years, with which hundreds of active ingredient fragments can be tested in protein crystals. These form the foundation for the subsequent development of an active ingredient. Due to our special expertise, the experimental sites at BESSY II are in great demand. Around 100 research teams regularly conduct experiments with us – including the group headed by Professor Rolf Hilgenfeld from the University of Lübeck, for whom we quickly found a place within a few days. There were only three days between the call from the Lübeck researchers and the measurement time with us.
Professor Hilgenfeld and his team have succeeded in decoding the 3D structure of an important protein from Sars-Cov-2 to BESSY. How did the researchers go about doing this?
At the beginning of January, after the genome of the novel coronavirus was sequenced, Rolf Hilgenfeld and his team were able to produce and crystallize a specific virus protein – the main viral protease – from the coronavirus. This protein is elementary in the life cycle of the corona virus ‘because it is involved in the multiplication of the viruses. With our instruments, the Lübeck researchers were then able to decode the three-dimensional structure of the main protease.
What is the role of the main viral protease?
When a virus attacks a cell, it reprograms the entire cell so that it produces virus proteins. These proteins initially arise as a very long polyprotein with many chains. The protease cuts this polyprotein into individual proteins. This is the only way the virus can multiply and infect other cells. Now we know the three-dimensional structure of the protease. This means that we have a blueprint, so to speak, to develop substances that inhibit the function of the protease. This is a major breakthrough: this is where researchers can start developing effective therapy. With this discovery, the search for a drug against the novel coronavirus can be significantly accelerated.
How will these results be used in the next step to develop an active ingredient?
The first step is to find known, already established drugs that match the active center of the protease and can block the protein. The advantage is obvious: These drugs have already been approved and only need to be expanded to include a new indication. This process is established in research. In this way, for example, it was possible to find active substances against HIV. Here too, the HIV protease was the focus of research. The drugs discovered at that time are still used today.
And new drugs?
Developing new substances naturally takes considerably longer. Here go several years. If you have found a molecule, you first have to check whether it is toxic or is broken down into toxins in the body. This is followed by numerous clinical studies: animal experiments, experiments with healthy people and finally experiments with volunteers. All of these processes are necessary for researchers to develop a safe drug.
zoom
Image: HZB / Michael Setzpfandt
–
Dr. Manfred Weiss heads the macromolecular crystallography group at the BESSY II synchrotron source at the Helmholtz Center Berlin. Using the high-intensity X-ray light from BESSY II, researchers at the University of Lübeck have decoded the three-dimensional structure of a key protein from SARS-CoV-2.
–
–
What exactly do the researchers do to crack the protein?
One method that we have established at the Helmholtz Center Berlin is the so-called fragment screening. We examine hundreds of small molecular substances and check which of them dock with a protease. Because the surface structure of the proteins is complicated. It is very difficult to find tailor-made molecules that prevent their function. With our approach, we test thousands of possible keys until we have found the “Dietrich” and can penetrate the protease. This is a pioneering approach to the development of a new drug, and that is exactly what we are currently exchanging with the research team from Lübeck.
Professor Hilgenfeld’s work has just been published in the scientific journal Science and was previously available to all researchers worldwide. Is this transparent open access access common?
In structural biology research, it is standard to provide the scientific community with new results very quickly. All academic researchers who take measurements with us are also committed to openly publishing their results and making them available to other researchers. At BESSY II we live from the fact that scientists use our infrastructure and examine their samples with us. For highly topical and relevant research questions, such as the search for an active ingredient against Sars-Cov-2, we also provide fast-track access to our jet pipes – this also applies to Professor Hilgenfeld and his team.
Press release BESSY II
Publication in the magazine Science
Protein crystallography on BESSY II
Press release from the University of Lübeck
–
