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Cocktail of REGN Antibodies Binds More Strongly to SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces Its Neutralizing Ability
[Image: see text] A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achie...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016775/ https://www.ncbi.nlm.nih.gov/pubmed/35403431 http://dx.doi.org/10.1021/acs.jpcb.2c00708 |
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author | Nguyen, Hung Lan, Pham Dang Nissley, Daniel A. O’Brien, Edward P. Li, Mai Suan |
author_facet | Nguyen, Hung Lan, Pham Dang Nissley, Daniel A. O’Brien, Edward P. Li, Mai Suan |
author_sort | Nguyen, Hung |
collection | PubMed |
description | [Image: see text] A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. Here, using all-atom steered molecular dynamics and coarse-grained umbrella sampling, we examine the interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with REGN10987 and REGN10933 separately as well as together. Both computational methods show that REGN10933 binds to RBD more strongly than REGN10987. Importantly, the cocktail binds to RBD (simultaneous binding) more strongly than its components. The dissociation constants of REGN10987-RBD and REGN10933-RBD complexes calculated from the coarse-grained simulations are in good agreement with the experimental data. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity. |
format | Online Article Text |
id | pubmed-9016775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90167752022-04-19 Cocktail of REGN Antibodies Binds More Strongly to SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces Its Neutralizing Ability Nguyen, Hung Lan, Pham Dang Nissley, Daniel A. O’Brien, Edward P. Li, Mai Suan J Phys Chem B [Image: see text] A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. Here, using all-atom steered molecular dynamics and coarse-grained umbrella sampling, we examine the interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with REGN10987 and REGN10933 separately as well as together. Both computational methods show that REGN10933 binds to RBD more strongly than REGN10987. Importantly, the cocktail binds to RBD (simultaneous binding) more strongly than its components. The dissociation constants of REGN10987-RBD and REGN10933-RBD complexes calculated from the coarse-grained simulations are in good agreement with the experimental data. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity. American Chemical Society 2022-04-11 2022-04-21 /pmc/articles/PMC9016775/ /pubmed/35403431 http://dx.doi.org/10.1021/acs.jpcb.2c00708 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Nguyen, Hung Lan, Pham Dang Nissley, Daniel A. O’Brien, Edward P. Li, Mai Suan Cocktail of REGN Antibodies Binds More Strongly to SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces Its Neutralizing Ability |
title | Cocktail of REGN Antibodies Binds More Strongly to
SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces
Its Neutralizing Ability |
title_full | Cocktail of REGN Antibodies Binds More Strongly to
SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces
Its Neutralizing Ability |
title_fullStr | Cocktail of REGN Antibodies Binds More Strongly to
SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces
Its Neutralizing Ability |
title_full_unstemmed | Cocktail of REGN Antibodies Binds More Strongly to
SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces
Its Neutralizing Ability |
title_short | Cocktail of REGN Antibodies Binds More Strongly to
SARS-CoV-2 Than Its Components, but the Omicron Variant Reduces
Its Neutralizing Ability |
title_sort | cocktail of regn antibodies binds more strongly to
sars-cov-2 than its components, but the omicron variant reduces
its neutralizing ability |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016775/ https://www.ncbi.nlm.nih.gov/pubmed/35403431 http://dx.doi.org/10.1021/acs.jpcb.2c00708 |
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