Structural Insights into the Rational Design of a Nanobody that Binds with High Affinity to the SARS-CoV-2 Spike Variant

The continuous emergence of severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)variants is still prolonging the global coronavirus disease 2019 pandemic. A dimerized variable domain of heavy chain of heavy chain antibody(VHH)P17 that has highly potent neutralizing activity against SARS-CoV-2 has been reported but the mode of interaction with the epitope remains unclear. Here, we report the complex structure of monomerized P17 bound to the SARS-CoV-2 receptor binding domain(RBD). The structure revealed details of the binding interface and showed that P17 had an appropriate linker length to have an avidity effect. Furthermore, we identified mutations that decrease the binding affinity of P17 and proposed methods for the acquisition of affinity toward the Omicron RBD.