Research team identifies ‘protective switches’ in SARS-CoV-2 protein that defend against immune system

More than 700 million people have been infected and nearly seven million have died, making SARS-CoV-2 the most devastating pandemic of the 21st century. COVID-19 vaccines and medications have been successful in mitigating the course of the disease in many people and containing the pandemic. However, the risk of new epidemics has not been avoided. The virus is constantly mutating, which allows it to infect human cells and multiply more and more efficiently. Additionally, it is developing various strategies against the human immune system as part of a “molecular arms race”.

A team led by researchers from the University of Göttingen has discovered various “protection switches” in the coronavirus that protect it from attacks by the immune system. The results are published in Natural communications.

Researchers have identified two previously unknown chemical protection switches in the virus’s main “protease,” a crucial coronavirus protein. The most important drug against COVID-19, called Paxlovid, targets this protein. The virus uses its main protease to eliminate other viral proteins in our infected cells, thereby driving its own replication. To do this, it uses the amino acid cysteine.

“From a chemical point of view, this could be an Achilles heel for the coronavirus, because cysteines can be destroyed by highly reactive oxygen radicals, which our immune system uses to fight viruses,” explains Professor Kai Tittmann , research group in molecular enzymology in Göttingen. University, who led and coordinated the study.

The protection switches mean that the virus’s main protease is protected from bombardment of the immune system by oxygen radicals: the protein is stabilized by a cysteine ​​forming a disulfide with an adjacent cysteine ​​via two sulfur atoms. This prevents the destruction of cysteine. At the same time, a bridge called SONOS connects three parts of the protein between sulfur atoms (S), oxygen atoms (O) and a nitrogen atom (N). This 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, an earlier discovered coronavirus – severe acute respiratory syndrome, also known as SARS-CoV-1 – which triggered the 2002 severe acute respiratory syndrome to 2004 outbreak, also has these switches protection. This is the first time this has been demonstrated.

Despite this scientific first, researchers did not just discover “protection switches”. With the chemical plan in hand, they set about searching for molecules that could bind precisely to “protection switches,” thereby inhibiting the virus’s main protease. They identified these molecules not only in the test tube, but also in infected cells.

“This type of molecule opens the way to new therapeutic interventions that will stop coronaviruses in their tracks,” says Lisa-Marie Funk, first author of the study, also at the Molecular Enzymology Research Group at the University of Göttingen.