DESY X-ray lightsource identifies promising candidates for COVID drugs

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 sick people. Viruses cannot reproduce on their own. Instead, they introduce their own genetic material into the cells of their host and cause them to produce new viruses. Proteins such as the main protease of the virus play an important role in this process. It cuts protein chains, which were 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 be interrupted under certain circumstances; the virus can no longer reproduce and the infection comes to a standstill.

High-tech in structural biology  fro thousends if candidates to the best two

The special technical equipment at the PETRA III station P11 includes a fully automated sample change with a robotic arm, so that each of the more than 7,000 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.

In a next step, the research group led by Yaiza Fernández-García from the Department of Virology at BNITM investigated whether these agents 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 antiviral activity with good cell compatibility. Therefore, cooperation partners have already started preclinical investigations with these two active substances.

New binding site identified

In their drug screening using protein crystallography, the researchers did not examine fragments of potential drugs as usual, but complete drug molecules. In the process, 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 positive 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 hot drug candidates binds precisely to this site," says Christian Betzel from the University of Hamburg, co-initiator of the study.
A particular strength of the X-ray screening method compared to other screening methods is that researchers obtain the three-dimensional structure of the protein-drug complexes as a result and can thus determine 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 central database for drug developments based on them.