SARS CoV-2 Spike Protein is the Main Antigen Target for Drug Development

The study used plasma from convalescent SARS CoV-2 patients to improve clinical outcomes. Human antibodies have also been isolated and used to counteract the neutralizing activity of SARS CoV-2 in vitro. Nanoantibody, a single domain antibody, can be used as an alternative therapeutic agent. Their small size, higher stability and production simplicity add great advantages to their functions. Previous studies have shown that nanoantibodies can neutralize viruses by inhibiting the binding of spike proteins to ACE2 receptors. Although it is usually extracted from immune camels, the development of synthetic nano antibody library can more effectively select the binding agent of the desired target.

In this study, nano antibody was synthesized to target the RBD of SARS CoV-2, and showed that it competed with ACE2 binding and neutralized SARS CoV-2 spike pseudovirus. Sybody 23 (Sb23) shows precise targeting by binding to recombinant RBD and perfusion spike glycoprotein with high affinity. Sb23 also showed effective neutralizing activity. Using the small angle X-ray scattering (SAXS) model of RBD-Sb23 complex, the synthesized nanoparticles bind near the ACE2 binding site on RBD. Low temperature electron microscope is used to reveal that Sb23 binds to the peak of ACE2 binding site on RBD in “up” and “down” conformation, thus effectively blocking ACE2 binding.

The generated synthetic nano antibody library aims to select highly specific binders with neutralizing activity to SARS CoV-2 and complete it within 2-3 weeks. Traditionally, it may take up to 6 weeks for Llama immunized nano antibody to be generated, and the whole process takes 3-4 months in total. The use of synthetic nano antibody platforms does not require any immune steps, and has generated a diverse but large library of adhesives. A large pool of binders helps to explain the naturally occurring antibody maturation, and only a portion of the purified antigen is needed for the selection process. In this library, 85 unique combinations were identified in one round of selection. The same synthetic nano antibody was not found, indicating the potential of selecting other high affinity adhesives.

Increasing the affinity and affinity of binders may be beneficial to the development of therapeutic agents. Combined with non overlapping synthetic nanosomes, the neutralization potential of Sb23 can increase the overall affinity for spike proteins. The fusion of Sb23 and Sb12 also showed the neutralization potential and affinity for RBD in the same range as Sb23-Fc or Sb42-Fc, which also indicated the potential of heterobivalent ligands.

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