Li T, Zhou B, Luo Z, Lai Y, Huang S, Zhou Y, Li Y, Gautam A, Bourgeau S, Wang S, Bao J, Tan J, Lavillette D, Li D

SARS-CoV-2 and its variants, such as the Omicron continue to threaten public health. The virus recognizes the host cell by attaching its Spike (S) receptor-binding domain (RBD) to the host receptor, ACE2. Therefore, RBD is a primary target for neutralizing antibodies and vaccines. Here, we report the isolation and biological ...

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and structural characterization of a single-chain antibody (nanobody) from RBD-immunized alpaca. The nanobody, named DL28, binds to RBD tightly with a K D of 1.56 nM and neutralizes the original SARS-CoV-2 strain with an IC50 of 0.41 ?g mL-1. Neutralization assays with a panel of variants of concern (VOCs) reveal its wide-spectrum activity with IC50 values ranging from 0.35 to 1.66 ?g mL-1 for the Alpha/Beta/Gamma/Delta and an IC50 of 0.66 ?g mL-1 for the currently prevalent Omicron. Competition binding assays show that DL28 blocks ACE2-binding. However, structural characterizations and mutagenesis suggest that unlike most antibodies, the blockage by DL28 does not involve direct competition or steric hindrance. Rather, DL28 may use a "conformation competition" mechanism where it excludes ACE2 by keeping an RBD loop in a conformation incompatible with ACE2-binding.

Date: Jun. 21, 2022

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