Research team identifies protective switch in SARS-CoV-2 virus protein
.With over 700 million people infected and almost seven million dead, the global spread of Covid-19 has been the most devastating pandemic of the 21st century to date. Vaccines and medication against the SARS-CoV-2 coronavirus have been able to mitigate the course of the disease in many people and contain the pandemic. However, the risk of further outbreaks has not been averted: The virus is constantly changing its blueprint. This enables it to infect human cells and multiply more and more effectively. In addition, it develops a variety of strategies against the human immune system in a molecular arms race. A team led by researchers from the University of Göttingen has now discovered various protective switches in the coronavirus that protect it from attacks by the immune system. The results have been published in the journal Nature Communications.
The researchers identified two previously unknown chemical -protective switches- in one of the most important proteins of the coronavirus: the so-called main protease. The most important drug against Covid-19 is directed against this protein: Paxlovid . The main protease cleaves other proteins of the virus in infected cells and thus drives its replication. It uses the amino acid cysteine to do this. -From a chemical point of view, this is an Achilles heel of the coronavirus, because cysteine can be destroyed by highly reactive oxygen radicals, which our immune system uses against the virus," explains Kai Tittmann from the Department of Molecular Enzymology at the University of Göttingen, who led and coordinated the study.
The -protective switches- arm the main protease against the -radical bombardment- of the immune system: On the one hand, the protein is stabilized by one cysteine forming a disulphide with an adjacent cysteine via two sulphur atoms. This prevents the cysteine from being destroyed. Secondly, a bridge known as SONOS connects three areas of the protein between sulphur atoms (S), oxygen atoms (O) and a nitrogen atom (N) and prevents radicals from damaging its three-dimensional structure. Tittmann says: -It is fascinating how chemically elegant and effective the coronavirus is in defending itself against the immune system. Interestingly, the original coronavirus SARS-CoV, which triggered a pandemic in 2002/2003, also has these protective switches. We are also showing this for the first time.
The researchers were not yet satisfied with the discovery of the -protective switches-. With the chemical blueprint to hand, they searched for molecules that bind precisely to the -protective switches- and inhibit the main protease. They identified such molecules not only in the test tube, but also in infected cells. -This type of molecule opens up new therapeutic possibilities for stopping coronaviruses," says Lisa-Marie Funk, first author of the study and member of the Department of Molecular Enzymology at the University of Göttingen.
Researchers from the Faculty of Biology and Psychology and the Faculty of Chemistry at the University of Göttingen, the University Medical Center Göttingen, the Max Planck Institute for Multidisciplinary Natural Sciences, the Hannover Medical School and the Universities of Düsseldorf, Hamburg and Lübeck took part in the interdisciplinary study. The study was funded by the Covid-19 Research Network Lower Saxony (COFONI) and the German Research Foundation.
Original publication: Funk et al. Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design .Nature Communications (2024). DOI: 10.1038/s41467’023 -44621-0
