A research team of drugs at the University of Bonn has found two families of active substances that inhibit the reproduction of the coronavirus SARS-CoV-2. The drug candidates are able to secrete the main enzyme of the virus, the so-called major protease. The study is based on laboratory tests. Extensive clinical trials are still needed for their further development as therapeutic drugs. The results are now published in the journal Cemie Angewandte.
In order for the coronavirus to reproduce SARS-CoV-2, it relies on the major protease as a major enzyme. First its genome has translated from RNA to a large protein strand. The main viral protease then breaks down this protein chain into smaller pieces, from which the new viral grains are formed. “The main protease is a promising starting point for the study of coronavirus drugs,” says Dr. Dr. Christa E. Müller from the Institute of Medicine at the University of Bonn. “If this enzyme is blocked, viral reproduction in the body’s cells is stopped.” The researcher is a member of the Interdisciplinary Research Field of “Life and Health” at the University of Bonn.
The chemistry chemists designed a large number of potential inhibitors based on the structure of the major protease and the way the important virus reproduction enzyme works. “An appropriate protector must bind tightly to the main protease in order to be able to block its active site,” says Dr. Dr. Michael Gütschow, who heads an independent research group on such defenders at the University of Bonn Institute of Medicine.
Fluorescent test system
Then the experimental phase began. The researchers developed a new test system for high-throughput screening. They provided a substrate for the main protease to which a reporter molecule was attached. When the protease sensitively cleared this bond, the fluorescence of the product was measured. However, if a simultaneous inhibitor succeeded in inhibiting the activity of the protease, there was no fluorescence. “For most of the test fertilizers, we did not look for enzyme inhibition. But on rare occasions in our complete trials, fluorescence was suppressed: These were the beats we had hoped for. looking for protectors of the viral protease, “reports Gütschow.
Like chewing gum at the catalytic center
The researchers’ high-dose screening showed two seemingly promising types of drugs. Custom combinations of the two classes were then synthesized. They adhere to the main protease as chewing gum and block the vital catalytic center, which prevents the main protease from replicating the virus. “Some fertilizers have other effects,” Müller reports. “They also block a human enzyme that helps the virus enter body cells.”
Participants contributed a very different experience to the study. “It is only through a great collaboration that we have been able to design, synthesize and identify suitable drug candidates biochemically,” Gütschow said. “The best fertilizers represent promising lead structures for drug development,” according to Müller. However, extensive clinical trials have not yet confirmed whether these candidates also inhibit the reproduction of coronavirus-2 SARS in humans, Gütschow adds.
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Magazine Reference:
Breidenbach, J., et al. (2021) Focusing on SARS Key Proteins – CoV – 2: From the Establishment of High Yield Screening to Tall Inhibitor Design. Chemie Angewandte International Edition. doi.org/10.1002/anie.202016961.