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Furin-Spaltstelle am SARS-CoV-2-Spike-Protein.
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Researchers in theoretical chemistry at the University of Siegen were able to calculate the initial processes of corona virus penetration into human cells with the help of the OMNI supercomputer. The findings of PD Drs Stephan Bäurle and Thanawat Thaingtamtanha could provide important approaches for corona drug development.
Drugs against Covid 19 are being researched all over the world. The more you know about the virus and how it spreads in the body, the easier it is to find starting points for treatment. Very intense work on this is currently underway in experimental laboratories. But simulations also play an important role. The chemical and cellular processes in an infection with the SARS-CoV-2 virus can be modeled with the computer. The prerequisite is a high-performance computer, such as that of the University of Siegen with the new OMNI cluster. This supercomputer offers PD Dr. Stephan Bäurle, who heads the working group for theoretical chemistry at the University of Siegen, the opportunity to work on elucidating the mechanisms of various diseases.
Together with his master’s student Thanawat Thaingtamtanha, Bäurle has now developed and used computational methods by which the initial processes of corona virus penetration into the human cell can be described at the atomic level, that is, the smallest. The researchers were able to simulate these processes so that new information is available on the fusion mechanism between the spines on the surface of the virus membrane and the membrane of human cells. In the computer simulation, you can follow how the process of infection and multiplication of the virus, which has entered the human body, begins at the molecular level. “Once you know this, you can try to detect weaknesses in the process to stop viral replication,” explains Bäurle. At this point, antiviral drugs could then begin. The advantage: their effect can also be estimated with the help of computer simulations before researchers undertake further experimental steps in the laboratory.
For the Siegen researchers, detailed knowledge of the molecular processes involved in the penetration of the corona virus into the host cell is a prerequisite for the development of new drugs. Two key proteases play major roles in the corona virus: TMPRSS2 and furin. Proteases are endogenous enzymes that act as “tools” at the molecular level. Furin works like scissors and causes specific proteins to be “cut” making them “active” in the cells. This activation is important for stimulating the body’s own processes. Corona viruses of the SARS-CoV-2 type, which are often depicted as round balls with sharp tips, unfortunately, unlike other corona viruses, have characteristic spots on these very tips (spike proteins) that signal furin that a cut must be made (so-called furin cleavage sites). Each spike protein consists of three subunits (heteromers), each with a furin cleavage site. The cleavage sites are at the end of each heteromer, where there is a kind of bifurcation in two branches (S1 and S2). Furin does what it’s supposed to do. It “cuts” a “branch” at the cleavage site, allowing the virus to enter the healthy cell. The propagation process can begin.
Using large-scale atomistic computations, Bäurle and his team were able to show this mechanism in more detail and describe how a “door” opens for the spike protein on the host cell’s cell membrane. An ACE-2 receptor acts as a “door opener”. “We were able to show that binding of the cellular ACE2 receptor to one of the tip heteromers leads to increased furin binding, which in turn promotes binding of the TMPRSS2 protease,” says Bäurle. From this it can be concluded that furin accelerates the fusion of the viral spine with the cell membrane, so that the virus can finally inject its genetic material into the host cell more easily and multiply there more easily.
The results of the work of the Theoretical Chemistry Working Group of the Department of Chemistry and Biology have only recently been published (https://link.springer.com/article/10.1007/s00894-022-05206-8). Bäurle hopes that the findings described may contribute to the development of therapies for patients – and not just for Covid 19. It has long been known that dysregulated furin activity leads to a variety of diseases such as cancer, diabetes, inflammation, disease. neurological and cardiovascular. “The results of our work indicate that risk factors associated with increased furin levels increase the virulence of SARS-CoV-2 virus infection,” says Bäurle.
Siegen’s scientists in theoretical chemistry were able to add a piece to the mosaic with their work on corona research. “We want to know more and make a contribution with our work in the fight against the virus. And through cooperation, for example with the human biology department of our university, but also through the exchange in wider research networks, it is possible to add more, “hopes the scientist.
PD Dr Stephan Bäurle and Thanawat Thaingtamtanha conduct research in the field of theoretical chemistry on the cellular processes involved in an infection with the SARS-CoV-2 virus.
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