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The ability of SARS-CoV-2 to infect cells depends on the interactions between the viral spike protein and the human cell surface protein ACE2. In order for the virus to attach to the cell surface, the spike protein ACE2 binds with the help of three finger-like protrusions, the so-called receptor binding domains (RBD). Blocking RBDs can therefore prevent the virus from entering human cells. This can be done with antibodies.
Nanobodies, small antibodies found in camels and llamas, show promise as anti-virus agents due to their high stability and small size. Although it is time-consuming to obtain them from animals, advances in technology now allow for rapid selection of synthetic nanobodies called sybodies. A technological platform for the selection of sybodies from large synthetic libraries was recently developed in the laboratory of Markus Seeger at the University of Zurich and made available for this study.
Looking for the best sybody against SARS-CoV-2
The Christian Löw group of the Hamburg EMBL has searched existing libraries for sybodies that could prevent SARS-CoV-2 from infecting human cells. Initially, they used the viral spike protein RBDs as bait to select the sybodies that would bind to them. Next, they tested the selected sybodies for their stability, efficacy and binding accuracy. Among the best binders, one called Sybody 23 was found to be particularly effective in blocking RBD.
To find out exactly how Sybody 23 interacts with viral RBDs, researchers from Dmitri Svergun’s group at EMBL in Hamburg analyzed the binding of Sybody 23 to RBDs using small-angle X-ray scattering. In addition, Martin Hällberg of the CSSB and the Karolinska Institutet used Kryo-EM to determine the structure of the complete peak of SARS-CoV-2 linked to Sybody 23. RBDs alternate between two positions: in the “up” position, the RBDs protrude , ready to bind ACE2; In the “down” position, they are curled up to hide from the human immune system. The molecular structures indicated that Sybody 23 binds RBDs in both the upper and lower positions, blocking the areas where ACE2 would normally bind. This ability to block RBDs regardless of their location may explain why Sybody 23 is so effective.
To test whether Sybody 23 could neutralize a virus, Ben Murrell’s team at the Karolinska Institutet used another virus called lentivirus which was modified to have the SARS-CoV-2 spike protein on its surface worn. They observed that Sybody 23 successfully inactivated the modified virus in vitro. Further tests are needed to confirm whether this Sybody can stop SARS-CoV-2 infection in the human body.
Scientific collaboration during the block
“The spirit of collaboration was huge in those days and everyone was motivated to contribute,” says Christian Löw, one of the study’s lead scientists. The researchers started the project as soon as they received approval from EMBL management to reopen their laboratories during the COVID-19 lockdown. They were able to select candidate sybodies and perform analyzes within weeks.
“It was only possible to get the results so quickly because the methods we used were already defined for other research projects that have nothing to do with SARS-CoV-2. Developing these tools would have required much more time and resources, “says Löw.
The results of this project promise a possible way to treat COVID-19. In future work, the scientists will conduct further analyzes to confirm whether Sybody 23 could be an effective COVID-19 treatment.
Reference: November 4, 2020, Nature Communications.
DOI: 10.1038 / s41467-020-19204-y.
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