Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a beta-coronavirus, caused the recent global Coronavirus Disease 2019 (COVID-19) pandemic. Among the virus-encoded proteins, the surface spike (S) protein is critical for viral entry, membrane fusion, and pathogenesis, and its receptor-binding domain (RBD) initiates viral entry by binding to a cellular receptor. This makes the S an important therapeutic target for COVID-19. SARS-CoV-2 mutates frequently, giving rise to five major variants of concern, among which the Omicron variant and its subvariants are less sensitive to current therapeutic antibodies. The first part of this review describes the main protein constituents of SARS-CoV-2 and their functions, the S protein-mediated viral entry and fusion processes, and the main SARS-CoV-2 variants. Nanobodies are single-domain antibodies with high target-binding affinity, strong stability, and low production costs, whose small size facilitates their access to protein regions that are inaccessible to conventional antibodies. Thus, in the second part, we comprehensively review SARS-CoV-2-targeting nanobodies, including those that bind specifically to the RBDs of the S proteins, non-RBD S proteins, and non-S proteins of variants and subvariants of SARS-CoV-2, with the hope that this information will be valuable for the generation of novel SARS-CoV-2-targeting nanobodies with improved potency against COVID-19.

Coronavirus  /  COVID-19  /  SARS-CoV-2  /  Variants  /  Spike protein  /  Receptor-binding domain  /  Nanobodies