A few SARS-CoV-2 NTD-targeting nAbs can cross-neutralize SARS-CoV infection, but with relatively lower neutralizing potency . similar to that of SARS-CoV, and a receptor-binding motif (RBM), which contacts with ACE2 receptor and is slightly different from that of SARS-CoV (Figure 1(c)) . In addition to RBD, the S1 subunit of SARS-CoV-2 also includes an N-terminal domain (NTD) (Figure 1(b)). While specific function of SARS-CoV-2 NTD in viral infection is still under investigation, Ademetionine neutralizing antibodies targeting this region have been identified . The S2 subunit contains heptad repeat region 1 (HR1) and 2 (HR2), both of which interact to form a six-helix bundle (6-HB) fusion Ademetionine core structure, bringing the viral and target cell membranes into close proximity for fusion (Figure 1(b,?,d)d) and 2(a) ). Therefore, S protein, including its fragments, RBD and NTD in S1 subunit as well as HR1 and HR2 in S2 subunit, can potentially serve as key therapeutic targets against SARS-CoV-2 infection (Figure 2). Here, we summarize recently developed therapeutic antibodies and peptide fusion inhibitors targeting these regions of SARS-CoV-2 S protein (Table 1). Figure 1. Schematic structures of SARS-CoV-2 virion, spike (S) protein and its functional domains. (a) SARS-CoV-2 virion contains a single-stranded RNA encoding four structural proteins, including S, envelope (E), nucleocapsid (N), and membrane (M) proteins. (b) Schematic structure of SARS-CoV-2 S protein and its functional domains. SP, signal peptide; NTD, N-terminal domain; RBD, receptor-binding domain; RBM, receptor-binding motif; FP, fusion peptide; HR1 and HR2, heptad repeat region 1 and 2; TM, transmembrane; CP, cytoplasmic tail. (c) Crystal structure of SARS-CoV-2 RBD complexed with angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6m0j). SARS-CoV-2 RBD core is colored in blue, RBM in red, and ACE2 in green. (d) Crystal structure of SARS-CoV-2 6-helix-bundle (6-HB) (PDB ID: 6lxt). HR1 is colored in cyan, and HR2 is colored in purple. Figure 2. Schematic structures of SARS-CoV-2 S protein-mediated receptor-binding and membrane fusion, as well as S-targeting therapeutic antibodies and peptide fusion inhibitors. (a) Schematic structures of SARS-CoV-2 S-mediated receptor-binding and membrane fusion processes. RBD in S1 subunit (S1-RBD) first binds cellular ACE2 receptor to form RBD/ACE2 complex (receptor binding stage), which triggers conformational changes of S protein, resulting in the dissociation of S1 subunit from the S2 subunit and exposure of HR1 and HR2-trimers (intermediate stage) in S2 subunit. This leads to the formation of a 6-helix bundle (6-HB) fusion core and further fusion of virus and cell membranes (membrane fusion). (b-d) Inhibitory mechanisms of SARS-CoV-2 S-targeting therapeutic antibodies and fusion inhibitors against virus infection. (b) Neutralizing antibodies (nAbs) targeting RBD protein bind the RBD, thus blocking RBD-ACE2 Ademetionine binding and subsequent formation of RBD/ACE2 complex. (c) nAbs targeting NTD in S1 subunit block conformational changes of S protein and subsequent processes. (d) S2-HR1-targeting fusion inhibitors bind the HR1, preventing the formation of 6-HB fusion core and membrane fusion. Table 1. Selected COVID-19 therapeutic antibodies and peptide fusion inhibitors targeting SARS-CoV-2 S Rabbit polyclonal to CD48 proteina. [6,15]. Generally, while SARS-CoV-2 RBD-targeting nAbs (such as CC6.33, COVA2-02, COV2-2678, and COV2-2514) potently neutralize SARS-CoV-2 infection, they have weak neutralizing activity against SARS-CoV infection [6,15,16]. 2.2. Therapeutic antibodies targeting NTD in S1 subunit of SARS-CoV-2 S protein The NTD is another target for the development of therapeutic antibodies against SARS-CoV-2 (Figure 2(c)). Several NTD-specific human mAbs, 4A8, 4C8, 2C17, 5C24, and COVA1-22, neutralize pseudotyped and live SARS-CoV-2 infection [4,12,15]. These NTD-targeting nAbs generally do not bind SARS-CoV-2 RBD, thus not directly blocking the RBD-ACE2 binding, but rather potentially restrain S conformational changes from the pre-fusion to post-fusion stages (Figure 2(c)) [4,15]. Previous studies on MERS-CoV also indicate that the NTD-targeting mAbs might inhibit viral entry and block receptor engagement at the cell membrane . Interestingly, some mAbs with potent SARS-CoV-2 neutralizing activity, such as 2C43, can bind both RBD and NTD, and block RBD-ACE2 interaction . It is worthy of noting that SARS-CoV-2 NTD-targeting nAbs usually have less neutralizing activity than RBD-specific nAbs against SARS-CoV-2 infection . A few SARS-CoV-2 NTD-targeting nAbs can cross-neutralize SARS-CoV infection, but with relatively lower neutralizing potency . Cryo-EM structures of complexes of 4A8/S and Ademetionine 4C8/S-trimer of SARS-CoV-2 are available [4,12], providing a structural information for understanding the binding site(s) of these mAbs Ademetionine in the S protein and their mechanisms of action against SARS-CoV-2.
A few SARS-CoV-2 NTD-targeting nAbs can cross-neutralize SARS-CoV infection, but with relatively lower neutralizing potency