Design and Characterization of Bivalent Molecules Against SARS-CoV2

Abstract The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compelled extraordinary attention to the development therapeutic reagents. favorable physical properties nanobodies make them attractive candidates for investigations their ability block viral entry. By X-ray crystallography we determined structural basis interaction a panel synthetic (Sb14, Sb16, Sb45 and Sb68) with SARS-CoV-2 receptor binding domain (RBD): binary complexes Sb16–RBD Sb45–RBD; ternary complex Sb14–RBD–Sb68, Sb45–RBD–Sb68. Sb16 bind RBD identical footprints ACE2, but complementarity determining regions (CDR)2 CDR3 are oriented diametrically oppositely. structure Sb45-RBD-Sb68 indicates that binds squarely at ACE2 interface, whereas Sb68 attaches toward interface's perimeter. configuration suggests several sybodies may capture sizable portion RBD's surface. These sybody structures provided insights were used create novel, highly potent biparatopic bivalent molecules scaffold mimicking miniproteins high affinity neutralize variants. Supported by Intramural research program NIAID/NIH