Fig. 3

Proposed anti-viral mechanism for antibodies and fusion inhibitors targeting S2. a An overview of SARS-CoV-2 spike conformation change and its mediated membrane fusion. After the standing RBD engages ACE2 and S1 subunit dissociates, S2ʹ site will expose and be cleaved by the host proteases, followed by the insertion of FP into host cell membrane and the formation of HR1-HR2 six-helix bundle (6-HB). Subsequently, membrane fusion occurs between viral particles and host cells. b–e Proposed mechanism of virus neutralization by anti-FP nAbs (b), anti-SH nAbs (c), HR2 or EK1-based peptides/lipopeptides (d), and 5-HB proteins (e). Anti-FP nAbs bind to the uncovered S2ʹ site and FP after S1 dissociation, inhibiting S2ʹ cleavage and/or preventing FP insertion into the host cell membrane. Anti-SH nAbs bind to SH in pre-S, disrupting 6-HB formation to prevent membrane fusion. 5-HB proteins bind to HR2 in pre-S trimer and HR2/EK1-based peptides bind to the HR1 groove in the intermediate state of S, both of which would block 6-HB formation. FP fusion peptide, HR1 heptad repeats 1, CH central helix, SH stem helix, HR2 heptad repeats 2, TM transmembrane domain, CT cytoplasmic tail, nAbs neutralizing antibodies, HB helix bundle, ACE2 angiotensin-converting enzyme 2