Synthetic nanobody-SARS-CoV-2 receptor-binding domain structures identify distinct epitopes

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• The global spread of SARS-CoV-2 necessitates novel therapeutic strategies.
• Understanding the interactions between viral proteins and host cell receptors is crucial for drug development.

Approach:

• X-ray crystallography was employed to determine the structures of synthetic nanobodies (sybodies) bound to the SARS-CoV-2 receptor-binding domain (RBD).
• Four distinct structures were analyzed: binary complexes (Sb16-RBD, Sb45-RBD), a ternary complex (Sb45-RBD-Sb68), and an unliganded sybody (Sb16).

Key Points:

• Sb16 and Sb45 bind the RBD at the ACE2 interface, with CDR2 and CDR3 loops oriented oppositely.
• Sb16 exhibits a significant CDR2 loop conformational change upon RBD binding.
• Sb68 binds peripherally to the ACE2 interface, with neutralization attributed to steric clashes with viral glycans.

Conclusions:

• The sybodies interact with different conformations of the SARS-CoV-2 spike (S) protein.
• Structural insights into sybody-RBD interactions can inform the design of targeted therapeutics.
• Understanding these binding mechanisms is vital for developing effective antiviral therapies against SARS-CoV-2.