Discovered Synthetic Nanobody “Sybodies” that Neutralizes SARS-CoV-2

Interfering with the interaction between the SARS-CoV-2 virus spike protein and its receptor, ACE2, in host cells has become a major target for COVID-19 treatment. Therapeutic neutralizing antibodies achieve this and constitute potential therapies. However, antibody production is traditionally a rather slow and costly process. Currently, a group of German researchers are reporting rapid isolation and characterization of Nanobodies from a synthetic library known as sybodies that targets the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. I will.

This work is published in Nature Communications In a paper titled “”Selection, biophysical, and structural analysis of synthetic Nanobodies that effectively neutralize SARS-CoV-2.“

To allow the virus to attach to the cell surface, the spike protein binds to ACE2 using three finger-like projections called the receptor binding domain (RBD). Therefore, blocking RBD may prevent the virus from invading human cells. This can be done using antibodies.

Nanobodies, small antibodies found in camels and llamas, are promising tools against viruses due to their high stability and small size. Obtaining them from animals can be time consuming, but advances in technology have enabled the rapid selection of synthetic Nanobodies called sybodies. In the laboratory of Dr. Markus Seeger, an assistant professor at the University of Zurich, a technical platform for selecting sybody from a large synthetic library has recently been developed and made available for this study.

Looking for the best sybody for SARS-CoV-2

The laboratory of Dr. Christian Löw, group leader at EMBL Hamburg, searched existing libraries to find a body that could prevent SARS-CoV-2 from infecting human cells. First, they used the viral spike protein RBD as food and selected those sybodies that bind to them. They then tested sybodies selected according to their stability, effectiveness, and binding accuracy. Among the best binders, what is called sybody23 has proved to be particularly effective at blocking RBD.

“Several binders with low nanomolar affinity and efficient neutralizing activity have been identified, of which Sb23 showed high affinity and showed IC-neutralized pseudoviruses.₅₀ “0.6 µg / mL”, the authors write.

To see exactly how sybody 23 interacts with the viral RBD, EMBL Hamburg senior scientist Dmitri Svergun, a PhD group of researchers, found that sybody 23 binds to RBD by small-angle X-ray scattering Was analyzed. In addition, Dr. Martin Hällberg of the Karolinska Institute used cryo-EM to determine the structure of the complete SARS-CoV-2 spike bound to sybody23.

The authors explained that the cryo-EM structure of spikes bound to sybody 23 indicates that “sybody 23 binds competitively at the ACE2 binding site.” “The reconstruction of the cryo-EM revealed an abnormal conformation of the spikes in which the two RBDs are in the” upper “ACE2-binding conformation,” they said.

RBD switches between two positions. In the “up” position, the RBD sticks out and is ready to bind ACE2. In the “bottom” position, they are rolled up to hide from the human immune system. The molecular structure revealed that sybody 23 binds to RBD at both “top” and “bottom” positions, blocking the region where ACE2 normally binds. This ability to block RBD regardless of position may explain why sybody23 is so effective.

Finally, to test whether sybody 23 can neutralize the virus, Ben Murrell’s group at the Karolinska Institute used another virus called the Lentivirus to surface the SARS-CoV-2 spike protein. Modified to carry to. They observed that sybody23 succeeded in neutralizing the modified virus in vitro. Additional tests are needed to see if this sybody can stop SARS-CoV-2 infection in the human body.

Scientific cooperation during the blockade

“At this time, the spirit of collaboration was so great that everyone was motivated to contribute,” says Löw. With approval from EMBL leaders, the researchers started the project as soon as they reopened the lab during the blockade of COVID-19. They managed to select candidate sybodies and performed the analysis in just a few weeks.

“The methodology we used was already established for other research projects unrelated to SARS-CoV-2, so it was possible to obtain results very quickly. Development of these tools. It took quite a lot of time and resources, “says Löw.

The results of this project have potential potential ways to treat COVID-19. In future studies, scientists will perform further analysis to see if sybody23 can be an effective treatment for COVID-19.