The ability of SARS-CoV-2 to infect cells depends on interactions between the viral spike protein and the human cell surface protein ACE2. To enable the virus to hook onto the cell surface, the spike protein binds ACE2 using three finger-like protrusions, called the receptor binding domains (RBDs). Blocking the RBDs therefore has the potential to stop the virus from entering human cells. This can be done using antibodies.<\/p>\n\n\n\n
Nanobodies, small antibodies found in camels and llamas, are promising as tools against viruses due to their high stability and small size. Although obtaining them from animals is time consuming, technological advances now allow for rapid selection of synthetic nanobodies, called sybodies. A technology platform to select sybodies from large synthetic libraries was recently developed<\/a> in the lab of Markus Seeger<\/a> at the University of Zurich, and made available for this study.<\/p>\n\n\n\n EMBL Hamburg\u2019s Christian L\u00f6w group<\/a> searched through the existing libraries to find sybodies that could block SARS-CoV-2 from infecting human cells<\/a>. First, they used the viral spike protein\u2019s RBDs as bait to select those sybodies that bind to them. Next, they tested the selected sybodies according to their stability, effectiveness, and the precision of binding. Among the best binders, one called sybody 23 turned out to be particularly effective in blocking the RBDs.<\/p>\n\n\n\n To learn exactly how sybody 23 interacts with the viral RBDs, researchers in the group of Dmitri Svergun<\/a> at EMBL Hamburg analysed the binding of sybody 23 to the RBDs by small-angle X-ray scattering<\/a>. In addition, Martin H\u00e4llberg<\/a> at CSSB and Karolinska Institutet used cryo-EM<\/a> to determine the structure of the full SARS-CoV-2 spike bound to sybody 23. The RBDs switch between two positions: in the \u2018up\u2019 position the RBDs poke out, ready to bind ACE2; in the \u2018down\u2019 position they are furled to hide from the human immune system. The molecular structures revealed that sybody 23 binds RBDs in both \u2018up\u2019 and \u2018down\u2019 positions, and blocks the areas where ACE2 would normally bind. This ability to block RBDs regardless of their position might explain why sybody 23 is so effective.<\/p>\n\n\n\n Finally, to test if sybody 23 can neutralise a virus, the group of Ben Murrell<\/a> at Karolinska Institutet used a different virus, called a lentivirus, modified such that it carried SARS-CoV-2\u2019s spike protein on its surface. They observed that sybody 23 successfully disabled the modified virus in vitro<\/em>. Additional tests will be necessary to confirm whether this sybody could stop SARS-CoV-2 infection in the human body.<\/p>\n\n\n\nIn search of the best sybody against SARS-CoV-2<\/h3>\n\n\n\n