Structural Basis of SARS-CoV-2 and SARS-CoV Antibody Interactions

Abstract

The 2019 coronavirus pandemic is still a major public health concern. Neutralizing antibodies (nAbs) represent a cutting-edge antiviral strategy. Here, we focus on SARS-CoV-2 and SARS-CoV and discuss the current antibody research progress against rampant SARS-CoV-2 infections. We provide a perspective on the mechanisms of SARS-CoV-2-derived nAbs, comparing these with existing SARS-CoV-derived antibodies. We offer insight into how these antibodies cross-react and cross-neutralize by analyzing available S-glycoprotein-antibody complex structures. We also propose ways of adopting antibody-based strategies -- such as cocktail antibody therapeutics against SARS-CoV-2-- to overcome the possible resistance of currently identified mutations, and to mitigate possible antibody-dependent enhancement pathologies. Overall, this review provides a platform for the progression of antibody and vaccine design against SARS-CoV-2 and possibly, future coronavirus pandemics.

The ACE2-binding Interface of SARS-CoV-2 Spike Inherently Deflects Immune Recognition

“…In contrast, ACE2IS binders (C3-3 and C4-3) that bound to the RBD but not to RBD-T indeed competed with ACE2-spike interaction and showed a neutralization effect against the SARS-CoV-2 virus ( Figure 3 (C)–(E)), as we predicted. Thus, although we note that some neutralizing antibodies that do not directly target the ACE2IS have been reported, 20 our binding assay using RBD-T is effective in quantifying neutralizing antibodies that target the ACE2IS.…”

“…We note that not all neutralizing antibodies would fail to bind to RBD-T, because some neutralizing antibodies do not directly bind to the ACE2IS. 20 A binding assay using the RBD and RBD-T is a straightforward method to determine whether antibodies recognize the ACE2IS or not, and thus we utilized the RBD-T as an epitope analysis tool for anti-RBD antibodies.…”

What do we know about the antibody responses to SARS-CoV-2?

“…The competitive ability of ACE2 has correlated well with the neutralizing activities of the antibodies, although the antibodies analyzed so far have recognized epitopes in S1, both for the RBD region and for the N-terminal domain (NTD), and for S2, especially of the IgG class ( Ju et al, 2020b , Liu et al, 2020a ). Antibodies directed against the RBD region can prevent interaction with the ACE2 receptor, destabilize prefusion or restrict the conformational change of the S protein, in all cases preventing the entry of the virus, while for antibodies directed against NTD and S2 is unknown the mechanism of action ( Gavor et al, 2020 ). Notably, antibodies identified in convalescent patients showed that only those targeting the RBD site with a dissociation constant (Kd) smaller or closer to that of ACE2/RBD showed potent neutralization effects against pseudoviruses and true SARS-CoV-2 virions ( Cao et al, 2020 ).…”

SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses

“…Other antibodies against the RBD bind outside of the RBS. Within S there are other epitopes targeted by neutralizing antibodies in the NTD and elsewhere (Gavor et al 2020;Liu et al 2020). Polyclonal antibody responses that target divergent epitopes are more robust against escape (Weisblum et al 2020).…”