Scientists identify promising COVID drug candidates

April 02, 2021

A team of researchers, including scientists from the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen, has identified several candidates for drugs against the SARS-CoV-2 coronavirus using the PETRA III X-ray light source at the German Electron Synchrotron (DESY). Among them are two promising compounds that are currently being investigated in preclinical studies. This drug screening – probably the largest of its kind – also revealed a new binding site on the virus.

Direct view of the sample in protein X-ray crystallography: The tiny pin (tip in the center) carries the crystal sample and is firmly fixed in the sample holder on the beamline P11.

In contrast to vaccines, which help healthy people fight off the virus, drug research is looking for compounds that slow down or stop the reproduction of the virus in the body of already infected people. Viruses cannot reproduce on their own and need the host cells. Viral proteins, such as the main protease of the virus, play an important role in this process. The protease cuts protein precursors, which are the result of host cell´s translation of the virus’ genetic blueprint, into smaller parts. The virus then uses these parts to replicate and produce new infectious viruses. If the main protease can be blocked, the cycle can possibly be interrupted; the virus can no longer reproduce and the infection is defeated.

In a so-called X-ray screening approach, the researchers under DESY´s leadership quickly tested almost 6000 active substances that already exist for the treatment of other diseases. To do this, they examined around 7000 samples that came from several drug databases.

37 drug candidates identified

Electron density map of the most antiviral active ingredient calpeptin (yellow) binding at the main protease of the coronavirus.

"With the help of a high-throughput method, we were able to find a total of 37 active substances that bind to the main protease," says Alke Meents from DESY, who initiated the experiments. 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 compounds to seven, two of which stood out in particular. These two were so effective that they are currently being further investigated in preclinical studies. “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 compounds,” explains DESY researcher Sebastian Günther, first author of the paper now published in the journal Science.

The beamlines used in these experiments – DESY beamline P11, as well as the EMBL beamlines P13 and P14 at DESY's PETRA III light source – specialize in structural biology. They allow the three-dimensional spatial structure of proteins to be visualized with atomic precision. "We first looked at whether and how the drugs 'dock' to the main protease, " explains Arwen Pearson, professor of biophysics at the University of Hamburg. Thanks to fully automated sample changing at the PETRA III stations, 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.

Novel binding site on the protease discovered

In their drug screening using protein crystallography, the researchers did not examine fragments of potential drugs as is usually the case but complete drug molecules. In the process, however, the team comprising more than 100 scientists also discovered something completely unexpected: They found a novel binding site on the main protease, which was unexplored as yet. "It was not only a positive surprise that we were able to discover a new drug binding site on the main protease, but that even one of the two promising drug candidates binds precisely to this site," says Christian Betzel, Professor of Biochemistry and Molecular Biology at the University of Hamburg.

"Only three to four months passed from the outbreak of the pandemic to the discovery of the first drug candidates, which could then be validated in cell cultures. This was only possible because of the cooperation of many scientists with a wide range of expertise," emphasizes Ashwin Chari, research group leader at the MPI for Biophysical Chemistry.

Researchers involved in the study come from DESY, the Bernhard Nocht Institute for Tropical Medicine, the Universities of Hamburg and Lübeck, the Fraunhofer Institute for Translational Medicine and Pharmacology, the Heinrich Pette Institute, the European XFEL, the European Molecular Biology Laboratory EMBL, the MPI for Biophysical Chemistry, the MPI for the Structure and Dynamics of Matter, the Helmholtz Center Berlin, and other institutions. (DESY/cr)

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