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

Abstract

The 2019 coronavirus pandemic remains a major public health concern. Neutralizing antibodies (nAbs) represent a cutting-edge antiviral strategy. We focus here on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, and discuss current progress in antibody research 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 structures of spike (S) glycoprotein-antibody complexes. 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 mutants and mitigate possible antibody-dependent enhancement (ADE) pathologies. This review provides a platform for the progression of antibody and vaccine design against SARS-CoV-2, and possibly against future coronavirus pandemics.

Keywords: COVID-19; S glycoprotein; SARS-CoV; SARS-CoV-2; antibodies; hACE-2.

Figure 1

Sequence Comparison of SARS-CoV and SARS-CoV-2 S Glycoproteins. (A) Bar diagram comparison of the S glycoprotein. For illustration purpose, the structure-based sequence alignment of (B) the NTD (PDB 5X4S), and (C) the RBD from human SARS-CoV (PDB 5WRG), civet SARS-CoV, and human SARS-CoV-2 (PDB 6VXX) were carried out using DALI and subsequently Clustal and ESPript. Secondary structures (α for helix, and β for strand) of the NTD and RBD indicated above the sequence. The residues of S glycoprotein that interact with mAbs 4A8 and B38 are highlighted in green (interacting with the NTD in panel B) and white (interacting with the RBD in panel C), respectively. The residues of human SARS-CoV and human SARS-CoV-2 that interact with the human ACE2 receptor are shown in bold red font in panel C. The RBD sequence alignment is highlighted in orange for S1_BCD and in cyan for the RBM. The percent identity matrix (PIM) for the NTD, the RBD (S1_BCD and RBM), S1BCD, and the RBM are indicated in the table. Note: these calculations were performed purely for illustration purposes in this review. Abbreviations: CP, cytoplasmic tail; FP, fusion peptide; HR1/2, heptad repeat 1/2; NTD, N-terminal domain; RBD, receptor-binding domain; RBM, receptor-binding motif; SARS-CoV, severe acute respiratory syndrome coronavirus; SP, signal peptide; TM, transmembrane.

Figure 2

Key Figure. SARS-CoV2 Antibodies Grouped Based on Targeting Region and Mechanism of Neutralization. (A) Antibodies binding to the RBM of the S (spike) protein that compete for hACE2 binding and block hACE2–RBD interactions. (B,C) Antibodies that bind to (B) the NTD or S2 and (C) the RBD (excluding RBM), but do not compete with hACE2 binding. These antibodies exhibit neutralization activity against the virus via unknown or multiple mechanisms. (D) Neutralizing antibodies that bind to the RBD and compete for hACE2 binding, either by restricting conformational changes or through steric hindrance, and that prevent the virus from interacting with the receptor. (E) Single antibodies or antibody cocktails that bind to multiple epitopes could also mediate virus neutralization by restricting conformational changes in S protein. Abbreviations: Abs, antibodies; CoVs, coronaviruses; hACE2, human angiotensin-converting enzyme 2; mAbs, monoclonal antibodies; NTD, N-terminal domain; pAbs, polyclonal antibodies; RBD, receptor-binding domain; RBM, receptor-binding motif; S1_BCD, S1_B core domain; S2, subunit 2.

Figure 3

Mapping of Antibody-Interacting Regions in the Trimeric S (Spike) Protein of SARS-CoV-2. (A) Illustration of coronavirus SARS-COV-2 S protein in trimeric form, showing its molecular surface representation (top and side view) (PDB: 6VXX). The NTD, S1_BCD, the RBM, other S1 subunit, and the S2 subunit are colored in green, blue, cyan, yellow, and grey respectively. Molecular surface representation of neutralizing antibodies (B) B38 human mAb (PDB: 7BZ5), (C) H014 humanized mAb (PDB: 7CAH), and (D) EY6A mouse mAb (PDB: 6ZER) targeting the RBD (S1_BCD and/or RBM) of S protein. (E) Molecular surface representation of human mAb 4A8 (PDB: 7C2L) interacting with the NTD of S protein. Panels B–E depict the S glycoprotein amino acids interacting with neutralizing antibodies (represented by sticks). The heavy and light chains of the indicated antibodies are represented in orange and light orange in the cartoon, respectively. For clarity, only one monomer of the trimer is shown. The SARS-CoV-2 virion ultrastructure was created by the Centers for Disease Control and Prevention (CDC) (Alissa Eckert, MS, and Dan Higgins, MAMS). Abbreviations: mAb, monoclonal antibody; NTD, N-terminal domain PDB, Protein Data Bank; RBM, receptor-binding motif; S1_BCD, S1_B core domain; SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.