Figure 1.

Life Cycle of Highly Pathogenic Human Coronaviruses (CoVs) and Specific Neutralizing Antibodies (nAbs) against These Coronaviruses.

(A) Life cycle of highly pathogenic human CoVs. These CoVs enter host cells by first binding to their respective cellular receptors [angiotensin-converting enzyme 2 (ACE2) for severe acute respiratory syndrome (SARS)-CoV-2 or SARS-CoV and dipeptidyl peptidase 4 (DPP4) for Middle East respiratory syndrome (MERS)-CoV] on the membranes of host cells expressing ACE2 (e.g., pneumocytes, enterocytes) or DPP4 (e.g., liver or lung cells including Huh-7, MRC-5, and Calu-3) via the surface spike (S) protein, which mediates virus–cell membrane fusion and viral entry. Viral genomic RNA is released and translated into viral polymerase proteins. The negative (−)-sense genomic RNA is synthesized and used as a template to form subgenomic or genomic positive (+)-sense RNA. Viral RNA and nucleocapsid (N) structural protein are replicated, transcribed, or synthesized in the cytoplasm, whereas other viral structural proteins, including S, membrane (M), and envelope (E), are transcribed then translated in the endoplasmic reticulum (ER) and transported to the Golgi. The viral RNA–N complex and S, M, and E proteins are further assembled in the ER–Golgi intermediate compartment (ERGIC) to form a mature virion, then released from host cells. (B) Potential targets of nAbs against SARS-CoV-2 and other pathogenic human CoVs. (a) Human CoV receptor binding and membrane fusion process. The CoV first binds a viral receptor (ACE2 or DPP4) through the receptor-binding domain (RBD) in the S protein, followed by fusion of the virus with cell membranes via the formation of a six-helix bundle (6-HB) fusion core. NTD, N-terminal domain. (b) Potential targets of nAbs on the S protein of human CoVs. Monoclonal antibody (mAb), antigen-binding fragment (Fab), single-chain variable region fragment (scFv), or single-domain antibody [nanobody (Nb) or VHH derived from camelid heavy chain antibody (HcAb)] binds to the RBD, S1 subunit (non-RBD, including NTD), or S2 of the viral S protein, blocking binding between the RBD and the respective receptor (for RBD-targeting nAbs), interfering with the conformational change of S (for S1-targeting nAbs), or hindering S2-mediated membrane fusion (for S2-targeting nAbs), leading to the inhibition of infection with pathogenic human CoVs in the host cells. This figure was created using BioRender (https://biorender.com/).