Researchers have discovered several promising drugs that may treat the new crown through X-ray screening

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Researchers have discovered several promising drugs that may treat the new crown through X-ray screening

The research team led by DESY in X-ray screening Nearly 6,000 known active substances have been tested in China. These substances already exist and can treat other diseases in a short period of time. Scientists stated in an article published in the online edition of Science today that after measuring about 7,000 samples, they were able to identify a total of 37 substances that can bind to the major protease (Mpro) of the SARS-CoV-2 virus. Seven of these substances can inhibit the activity of proteins and slow down the speed of virus proliferation. And two of them are very promising and are currently undergoing further preclinical research. This drug screening-probably the largest of its kind-also found a new binding site on the virus’s main protease.

Different from vaccines that help healthy people resist the virus, drug research is looking for drugs that slow or prevent the virus from multiplying in the body of an infected person. Viruses cannot reproduce by themselves. On the contrary, they need to introduce their own genetic material into the cells of the host in order for them to produce new viruses. Proteins such as the main protease of the virus play an important role in this process. The protease cuts the protein chain produced by the host cell according to the blueprint of the virus’s genetic material into smaller parts necessary for virus replication. If the main protease is blocked, the circulation may be interrupted, the virus can no longer reproduce, and the infection is defeated.

Beamline P11 of DESY’s PETRA III research light source specializes in structural biology research. Here, the three-dimensional structure of the protein can be imaged with atomic precision. The research team led by DESY physicist Alke Meents used this special ability to test thousands of active substances to see if and how they “dock” to the main protease-this is the first way to block it. An important step. Since these active substances have been approved for human treatment or are currently being tested, suitable drug candidates for the fight against SARS-CoV-2 can be used in clinical trials faster, which can save months or years of drugs Development time.

The robotic device on the beamline completed more than 7000 measurements in about 3 minutes. The research team quickly separated the wheat from the chaff with the help of automatic data analysis. “Using a high-throughput method, we found a total of 37 active substances that bind to major proteases,” said Meents, who initiated the experiment.

Lourdu Xavier, a research co-author from the MPSD International Max Planck Institute for Research, described the process as follows: “The challenging part is to screen out more than 6000 drugs using single crystal screening methods. It requires Dozens of people work 24 hours a day for several weeks, cultivating crystals, soaking them with drugs, capturing, freezing the crystals and loading them into the robotic workstation for X-ray scanning. This is a marathon and relay race. This is an amazing team effort , I’m very happy that we have found some drugs.

“As these exciting results enter preclinical trials, we also have sufficient conditions to take advantage of the room temperature of the XFEL pulse on the binding mechanism of allosteric drugs. A deeper understanding of dynamics will be developed, and XFEL pulses will be used to obtain millions of diffraction patterns in a short period of time. ”

After that, researchers from the Bernhard Nocht Institute of Tropical Medicine conducted research on whether these active substances can inhibit or even prevent virus replication in cell culture and how they are compatible with host cells. The work reduced the number of suitable active substances to seven, of which two are particularly prominent. “The active substances Calpeptin and Pelitinib clearly show the highest antiviral ability and good cell compatibility. Therefore, our partners have already started preclinical research on these two substances,” said DESY researcher Sebastian Günther.

When using protein crystallography for drug screening, the researchers did not perform as usual. They checked fragments of potential drugs. On the contrary, they checked the complete drug molecule. However, in the process, a team of more than 100 scientists also discovered something completely unexpected: they found a previously complete drug on the main protease. Unknown binding site.

“Even if these two most promising drug candidates do not enter clinical trials, the 37 substances that bind to the main proteases will form a valuable tool for drug development based on them. Database,” said Patrick Reinke, a DESY researcher and co-author of the publication.