Researchers has identified several candidates for drugs against the coronavirus SARS-CoV-2 at DESYs high-brilliance X-ray lightsource PETRA III

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A team of researchers has identified several candidates for drugs against the coronavirus SARS-CoV-2 at DESY´s high-brilliance X-ray lightsource PETRA III. They bind to an important protein of the virus and could thus be the basis for a drug against COVID-19.

In a so-called X-ray screening, the researchers, under the leadership of DESY, tested almost 6000 known active substances that already exist for the treatment of other diseases in a short amount of time.

After measuring about 7000 samples, the team was able to identify a total of 37 substances that bind to the main protease (Mpro) of the SARS-CoV-2 virus, as the scientists report online today in the journal Science.

Seven of these substances inhibit the activity of the protein and thus slow down the multiplication of the virus. Two of them do this so promisingly that they are currently under further investigation in preclinical studies.

This drug screening – probably the largest of its kind – also revealed a new binding site on the main protease of the virus to which drugs can bind.

In contrast to vaccines, which help healthy people to defend themselves against the virus, drug research is looking for drugs that slow down or stop the reproduction of the virus in the body of people who are already infected. Viruses cannot reproduce on their own. Instead, they introduce their own genetic material into the cells of their host and make them produce new viruses. Proteins such as the main protease of the virus play an important role in this process.

Protease cuts protein chains produced by the host cell according to the blueprint of the virus genetic material into smaller parts that are necessary for the reproduction of the virus. If the main protease can be blocked, the cycle can possibly be interrupted; the virus can no longer reproduce and the infection is defeated.

Beamline P11 of DESY´s PETRA III research lightsource specializes in structural biology studies. Here, the three-dimensional structure of proteins can be imaged with atomic precision.

The research team led by DESY physicist Alke Meents used this special capability to examine several thousand active substances from a library of the Fraunhofer Institute for Translational Medicine and Pharmacology and another library from the Italian company Dompé Farmaceutici SpA to see whether and how they “dock” to the main protease – the first important step in blocking it. Like a key in a lock, the drug molecule fits into a binding center of the protease.

The advantage of the drug library is that it contains active substances that have already been approved for the treatment of humans or those that are currently in various testing phases. Suitable candidates to combat SARS-CoV-2 could therefore be used in clinical trials considerably faster, saving months or years of drug development.

The special technical equipment at the PETRA III station P11 includes fully automated sample changes with a robotic arm, so that each of the more than 7000 measurements took only about three minutes. With the help of automated data analysis, the team was able to quickly separate the wheat from the chaff. “Using a high-throughput method, we were able to find a total of 37 active substances that bind with the main protease,” says Meents, who initiated the experiments.

A team of researchers has identified several candidates for drugs against the coronavirus SARS-CoV-2 at DESY´s high-brilliance X-ray lightsource PETRA III. They bind to an important protein of the virus and could thus be the basis for a drug against Covid-19. In a so-called X-ray screening, the researchers tested almost 6000 known active substances that already exist for the treatment of other diseases. The team was able to identify a total of 37 substances that bind to the main protease (Mpro) of the SARS-CoV-2 virus, as the scientists report in the journal Science. Seven of these substances inhibit the activity of the protein and thus slow down the multiplication of the virus. Two of them do this so promisingly that they entered preclinical studies. This drug screening – probably the largest of its kind – also revealed a new binding site for active substances on the main protease of the virus. Credit: DESY, Liza Arbeiter

In a next step, the researchers at the Bernhard Nocht Institute for Tropical Medicine investigated whether these active substances inhibit or even prevent virus replication in cell cultures and how compatible they are for the host cells. This reduced the number of suitable active substances to seven, two of which stood out in particular.

“The active substances Calpeptin and Pelitinib clearly showed the highest antivirality with good cell compatibility. Our cooperation partners have therefore already started preclinical investigations with these two substances,” explains DESY researcher Sebastian Günther, first author of the Science publication.

In their drug screening using protein crystallography, the researchers did not examine fragments of potential drugs as is usually the case, but complete molecules of the drug. In the process, however, the team of more than 100 scientists also discovered something completely unexpected: they found a binding site on the main protease that had been completely unknown until then.

“It was not only a nice surprise that we were able to discover a new drug binding site on the main protease—a result that can really only be achieved at a synchrotron light source like PETRA III—but that even one of the two promising drug candidates binds precisely to this site,” says Christian Betzel from the excellence cluster CUI of the University of Hamburg, co-initiator of the study.

“A particular strength of our method of X-ray screening compared to other screening methods is that we obtain the three-dimensional structure of the protein-drug complexes as a result and can thus identify the binding of the drugs to the protein at the atomic level.

Even if the two most promising candidates do not make it into clinical trials, the 37 substances that bind to the main protease form a valuable database for drug developments based on them,” explains Patrick Reinke, DESY researcher and co-author of the publication.

“The investigations at PETRA III impressively show how relevant high-brilliance synchrotron lightsources are for the development of future medicines and for health research as a whole,” stresses Helmut Dosch, Chairman of the DESY Directorate. “We must and want to expand our infrastructures even more in the future to cope with health crises like the current one.”


DESY and its campus partners join the global fight against the pandemic

The corona crisis also poses enormous challenges for science: New findings and concrete solutions for the SARS-CoV-2 pathogen are required within a very short time. DESY’s X-ray light sources are ideal tools for studying the virus and possible drugs at the molecular level. Researchers from DESY and its campus partners also contribute their expertise in other fields. Experts on the DESY campus are involved in corona research in many different ways:

  • At DESY’s X-ray source PETRA III, a research team screened several thousand active substances for their basic suitability as Covid-19 drugs. In the process, they identified several substances that block an enzyme that is important for virus replication. Another research group identified a synthetic antibody among hundreds of candidates that could neutralise the virus.
     
  • Using an X-ray procedure developed for the brain, researchers used PETRA III to examine damaged lung tissue of Covid-19 patients in extreme detail.
     
  • DESY’s IT departments make parts of their computing capacity available for data analyses and complex computer simulations. Among other things, they calculate how certain viral proteins behave. Up to 30 September 2020 alone, 13,997,439 hours of CPU time were thus accumulated, which corresponds to the full performance of about 800 laptops and about six percent of the total DESY computing capacity.
     
  • With the help of PETRA III, experts are looking for innovative ways of administering corona drugs. The aim is to alleviate possible side effects.
     
  • The Mainz-based company BioNTech, the developer of one of the first corona vaccines, is using PETRA III to look for ways to improve the still young class of RNA vaccines.
     
  • DESY theorists have modelled the propagation behaviour of SARS-CoV-2 with big-data models. One of the results was an algorithm that tracks the development of immunity and has the potential to reduce the burden on clinics.
     
  • Several teams on the DESY campus are working on rapid corona tests with which the virus can be detected faster, easier and cheaper than is currently possible.
     
Aufklärung der Proteinstruktur mit Röntgenlicht / Structural analysis of biomolecules with X-ray radiation

Structural analysis of biomolecules with X-ray radiation: Fast electrons (blue) from a particle accelerator are sent into an undulator (left) equipped with powerful magnets (green and violet). The electrons race past the magnets in a slalom pattern. In the process, the particles emit high-energy X-ray radiation (orange), which is directed through X-ray optics at a crystal (centre) made up of biomolecules. The crystal diffracts the X-ray radiation, thus generating a characteristic diffraction pattern on the detector (right). On the basis of this diffraction pattern, the structure of the biomolecules under investigation can be calculated down to the last atom (far right). Illustration: DESY, Cyprian Lothringer


More information: Sebastian Günther et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science, 2021; DOI: 10.1126/science.abf7945

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