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Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern.
Front Immunol. 2021; 12:691715.FI

Abstract

Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.

Authors+Show Affiliations

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.Disease Intervention & Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, United States.Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, United States.Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34149735

Citation

Deshpande, Ashlesha, et al. "Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern." Frontiers in Immunology, vol. 12, 2021, p. 691715.
Deshpande A, Harris BD, Martinez-Sobrido L, et al. Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern. Front Immunol. 2021;12:691715.
Deshpande, A., Harris, B. D., Martinez-Sobrido, L., Kobie, J. J., & Walter, M. R. (2021). Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern. Frontiers in Immunology, 12, 691715. https://doi.org/10.3389/fimmu.2021.691715
Deshpande A, et al. Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern. Front Immunol. 2021;12:691715. PubMed PMID: 34149735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern. AU - Deshpande,Ashlesha, AU - Harris,Bethany D, AU - Martinez-Sobrido,Luis, AU - Kobie,James J, AU - Walter,Mark R, Y1 - 2021/06/04/ PY - 2021/4/6/received PY - 2021/5/21/accepted PY - 2021/6/21/entrez PY - 2021/6/22/pubmed PY - 2021/6/25/medline KW - ACE2 binding affinity KW - RBD KW - SARS-CoV-2 KW - epitope mapping KW - neutralizing antibodies KW - variant of concern SP - 691715 EP - 691715 JF - Frontiers in immunology JO - Front Immunol VL - 12 N2 - Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/34149735/Epitope_Classification_and_RBD_Binding_Properties_of_Neutralizing_Antibodies_Against_SARS_CoV_2_Variants_of_Concern_ DB - PRIME DP - Unbound Medicine ER -