University of Bern: SARS-CoV-2 model improves drug research and development

Even if sufficient vaccines are now available worldwide and other drugs are coming onto the market, there is still a risk that new variants of SARS-CoV-2 will emerge that are even more infectious or that cannot be protected by the vaccines. The faster the properties of such variants can be characterized, the faster countermeasures can be taken.

Research on SARS-CoV-2 must be carried out in laboratories with a high level of biosafety, which is time-consuming and even rules out certain types of experiments. These experiments include, for example, the genetic screening of cell components that are essential for virus infection and reproduction and therefore represent some of the best targets for drugs.

Disarmed virus
Now researchers under the direction of Charles M. Rice from Rockefeller University, one of the winners of last year’s Nobel Prize in Medicine, and Volker Thiel from the University of Bern and the Institute for Virology and Immunology, have developed a new model of SARS-CoV-2. This separates the spike protein and the “multiplication machinery” of the coronavirus. The trick that the researchers used is that they put the entire coronavirus genome together without the spike protein in the laboratory and also insert a second “blueprint” with which the spike protein is produced into the cells.

Once introduced into the cells, the “spike-less” coronavirus blueprint, also called replicon RNA, can go through all steps of the viral life cycle, but cannot produce any new infectious coronavirus particles. Only when the same cells receive the spike gene can they secrete virus-like particles that are provided with spike proteins. These particles contain the entire viral genome except for the blueprint for the spike protein – this remains in the producing cells. The newly created particles can then be used to infect other cells, mimicking a natural infection. However, these newly infected cells also do not have the blueprint for the spike protein and can therefore not produce any new virus particles themselves, which in turn could infect other cells. In this way, minor precautionary measures can be taken in the laboratory with regard to biological safety. The study for the new model has now been published in the science magazineScience published.

Decisive advantage
“Similar systems have been presented before, but there is a crucial difference between these and ours,” says Volker Thiel, last author of the study together with Charles M. Rice. In the previously published systems, the SARS-CoV-2 genome was also divided into two parts – also into a part that contained the entire genome except for one protein that is important for the assembly of the virus. This protein was also produced separately. However, this was not the spike protein. Thanks to the new model, properties of the spike protein can now be better investigated. This is a great advantage: “Mutations in the spike protein have so far been the greatest cause for concern about new variants,” explains Thiel.

Easier and safer to use
“Changing one or the other part of the split genome may not sound like a big deal, but it is,” emphasizes Thiel. The entire SARS-CoV-2 genome consists of around 30,000 letters, which makes it difficult to handle, change and produce yourself, despite modern molecular biological methods. The genomic blueprint of the spike protein consists of fewer than 5,000 letters and is therefore much easier to handle and change. “In our model, the smaller spike genome part of the virus, in which most of the mutations that lead to problems occur, can be handled relatively easily, while the larger, second part of the genome remains constant,” explains Thiel.

Thanks to this mimicking of SARS-CoV-2, the simultaneous investigation of the properties of the spike protein and the “propagation machinery” is made considerably easier. The researchers were able to compare the new system with the natural virus and show that, for example, the effects of antiviral drugs can be investigated in a similar way. The model was blocked by existing antiviral drugs in the same way as the natural virus. “This means that the model can also be used to test new active ingredients – albeit under much safer conditions,” says Thiel.