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Review
. 2021 May 26;7(5):757-767.
doi: 10.1021/acscentsci.1c00216. Epub 2021 Apr 19.

Molecular Aspects Concerning the Use of the SARS-CoV-2 Receptor Binding Domain as a Target for Preventive Vaccines

Yury Valdes-Balbin  1 , Darielys Santana-Mederos  1 , Françoise Paquet  2 , Sonsire Fernandez  1 , Yanet Climent  1 , Fabrizio Chiodo  3   4 , Laura Rodríguez  1 , Belinda Sanchez Ramirez  5 , Kalet Leon  5 , Tays Hernandez  5 , Lila Castellanos-Serra  6 , Raine Garrido  1 , Guang-Wu Chen  7 , Dagmar Garcia-Rivera  1 , Daniel G Rivera  8 , Vicente Verez-Bencomo  1
Affiliations
Review

Molecular Aspects Concerning the Use of the SARS-CoV-2 Receptor Binding Domain as a Target for Preventive Vaccines

Yury Valdes-Balbin et al. ACS Cent Sci. .

Abstract

The development of recombinant COVID-19 vaccines has resulted from scientific progress made at an unprecedented speed during 2020. The recombinant spike glycoprotein monomer, its trimer, and its recombinant receptor-binding domain (RBD) induce a potent anti-RBD neutralizing antibody response in animals. In COVID-19 convalescent sera, there is a good correlation between the antibody response and potent neutralization. In this review, we summarize with a critical view the molecular aspects associated with the interaction of SARS-CoV-2 RBD with its receptor in human cells, the angiotensin-converting enzyme 2 (ACE2), the epitopes involved in the neutralizing activity, and the impact of virus mutations thereof. Recent trends in RBD-based vaccines are analyzed, providing detailed insights into the role of antigen display and multivalence in the immune response of vaccines under development.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Y.V.-B., D.S.-M, S.F., L.R., B.S.-R., K.L., D.G.-R., D.G.R., and V.V.B. are co-inventors on provisional SARS-CoV-2 vaccine patents including results covered here.

Figures

Figure 1
Figure 1
RBD–ACE2 interaction. (A) Transparent surface and ribbon representation of the SARS-CoV-2 RBD (residues Arg319–Phe541) complexed to the ACE2 N-terminal peptidase domain (residues Ser19–Asp615). The interface ACE2–RBD is colored in green and red, respectively, and the RBM in pink. The arrows indicate four different disulfide bridges able to stabilize the RBD. (B) Amino acids of ACE2 directly interacting with RBD (green). (C) Amino acids of RBD directly interacting with ACE2 (red).
Figure 2
Figure 2
Selected mutations in RBD. (A) Location of each mutated amino acid with respect to the RBM surface (pink). Residues belonging to the ACE2 epitope are highlighted in red, and those without contact with ACE2 are colored in blue. (B) and (D) New interactions associated with N501Y and E484K mutations, respectively. (C) Potential epistatic mutation Q498R associated with N501Y.
Figure 3
Figure 3
RBD epitopes of NAbs and location of the important mutations. (A) Example of antibodies of type 1. NAbs B38 and S2H14 interact with their respective epitopes overlapping the ACE2-binding region. (B) RBD surface (red) delimited by residues interacting with ACE2. (C) Example of antibodies of type 2. NAbs BD23, Fab2-4, S2H13, and P2B-2F6 interact with epitopes exposed in the RBD-down and RBD-up conformations.
Figure 4
Figure 4
(A) Electrostatic potential (red −10, +10 blue) and (B) hydrophobicity (green −20, +20 gold) maps represented on surfaces of the WT RBD and selected mutated RBD. Small circles show the biggest changes induced by mutation.
Figure 5
Figure 5
(A) Comparison of the B-cell response with different types of RBD immunogens. The multivalent RBD display permits cross-linking B-cell receptors leading to a more intense signaling. (B) Representation of the constructions of multivalent-displayed RBD immunogens by chemical conjugation, self-assembling, and ligation processes.
See this image and copyright information in PMC

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