XFEL: Pulling Together: A collaborative research approach to study COVID-19

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2020/06/17
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Pulling Together: A collaborative research approach to study COVID-19

European XFEL scientist Kristina Lorenzen talks about the COVID-19 related research currently going on at the facility

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Kristina Lorenzen, manager of the biolabs at European XFEL. Copyright: European XFEL

Around the world research facilities are quickly mobilizing resources, reshaping research programs, setting up collaborations and channeling time and energy into the global research effort to understand the novel Coronavirus, SARS-CoV-2. Even though European XFEL has been in reduced operation mode for the past few months, scientists at the facility have been working hard to get several COVID-19 related research projects up and running. Currently European XFEL is contributing to three projects ranging from basic research to application orientated, all based in the biological laboratories. Kristina Lorenzen, manager of the biolabs at European XFEL, explains what has been going on.

How did you start to get involved in these projects?

Together with several different collaborators we discussed already early in the year how we could contribute to corona related research efforts. We have these wonderful lab facilities here at European XFEL, so of course we should use them. The first step, however, was to put together a safety concept of how we could work in the labs while sticking to the hygiene and distance regulations. The safety of our staff is our main priority. Then we put together a research concept for COVID-19 related research, and eventually we got three projects off the ground.

Can you tell us more about these projects?

The collaboration with our colleagues on the DESY campus is probably the easiest to grasp. The project is aimed at identifying a potentially suitable antiviral drug. Together with several collaborators mainly located on the DESY campus they are looking at four different proteins – two from the SARS-CoV-2 virus and two from human cells. Their plan is to check how these proteins bind to a range of different drug compounds. So far they have done the screening on the first protein and are now validating the data. The second viral protein doesn’t seem to behave as nicely as the first and it’s proving a lot harder to produce it. Three different groups, including us, are now working on different techniques to try and produce this protein in the lab.

How did the screening of the first viral protein go?

That was a huge and impressive effort, even without the current restrictions due to corona. They produced a lot of protein crystals – something like 10000 tiny crystals - which all had to be fished out of their trays manually with tiny loops once they had been soaked in a solution with the compounds. Our collaborators worked in shifts to fish the crystals. That’s hard work! These were then put into the PETRA III beamlines at DESY and X-ray diffraction images made of the protein structures. Not all crystals diffract so they got data from about 3600 crystals in the end. In about 17 of those they could see that the viral protein bound to a potential drug target.

I have now done native mass spectrometry experiments on the protein alone and together with the 17 compounds. Mass spectrometry is like a very precise scale where you can measure the masses of the proteins and identify if and how well something has bound to them. Two of these 17 compounds bound very tightly to the protein, several others were loosely bound.

 

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European XFEL scientists are currently contributing to three COVID-19 related research projects, all based in the biolabs. Copyright: European XFEL

Does that mean that those two compounds can now be developed to antiviral drugs against SARS-CoV-2?

Not quite. Of course it would be cool if it did, and we hope to find something but a hit doesn’t mean that we have a useful drug. We also have to keep in mind how useful the drug is as well. All the compounds are approved drugs, or at least in final stage clinical trials. But some have terrible side effects, or maybe need to be administered in such high concentrations to actually have an effect that it wouldn’t be safe to give it to humans. So several partners are now doing follow ups – for example colleagues at the Bernard Nocht Institute in Hamburg are doing in vitro assays to see how these drugs affect the behavior of the virus and what concentrations are needed for it to be effective. And even those other loosely bound compounds could have an effect. They could, for example, inhibit that the protein binds somewhere else, or mean that it isn’t so reactive. We’re not there yet!

What about the other two projects European XFEL is involved in?

The other two projects are more basic research in focus. Together with colleagues at the Heinrich Pette Insititute we are looking at so-called non-structural proteins in the coronavirus. Of course they have a structure but are not part of the viral structure – the hull, the membrane etc. The ones we are interested in are involved in translating the viral proteins from the viral genetic code – RNA. It is known that a complex of three non-structural proteins translates the RNA into proteins, but we think the structural organization of these proteins is different than has been published in the literature. We are working on expressing two of these three proteins, using the enzyme, or protease, that the virus also uses to cleave the amino acid chain into functional sections to assemble these proteins. We are trying to make sure our experimental set-up resembles the viral environment as much as possible so we feel certain the data we get resembles that which would be seen in the virus. If we manage to get proteins soon we will probably send the crystals to DESY to be measured and see if we can resolve the structure of this complex.

The third project is a longer term project working on expressing viral proteins in insect cells. For this we are working with Lars Redecke and his group at the University of Lübeck who we have worked with in the past. This is an interesting alternative method for when perhaps it is difficult to get a protein to crystalise.

Will you also study these proteins on one of the European XFEL instruments?

The biolabs are designed to support the research done at the SPB instrument. At the moment we do not have any X-ray beam so the instruments are not operational, but our colleagues are working now to get the European XFEL back up and running and we are opening our own call for COVID-19 related research. As soon as the European XFEL is operational again more COVID-19 related research will be carried out at the instruments as well.