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Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein
Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the vi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181698/ https://www.ncbi.nlm.nih.gov/pubmed/35682988 http://dx.doi.org/10.3390/ijms23116309 |
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author | Weißenborn, Lucas Richel, Elie Hüseman, Helena Welzer, Julia Beck, Silvan Schäfer, Simon Sticht, Heinrich Überla, Klaus Eichler, Jutta |
author_facet | Weißenborn, Lucas Richel, Elie Hüseman, Helena Welzer, Julia Beck, Silvan Schäfer, Simon Sticht, Heinrich Überla, Klaus Eichler, Jutta |
author_sort | Weißenborn, Lucas |
collection | PubMed |
description | Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide. Furthermore, the proteolytic stability of the cyclic peptide was substantially improved, rendering it a better potential candidate for SARS-CoV-2 therapy. In a more mechanistic approach, the peptides also served as tools to dissect the role of individual mutations in the RBD for the susceptibility of the resulting virus variants to neutralization by the peptides. As the peptides reported here were generated through chemical synthesis, rather than recombinant protein expression, they are amenable to further chemical modification, including the incorporation of a wide range of non-proteinogenic amino acids, with the aim to further stabilize the peptides against proteolytic degradation, as well as to improve the strength, as well the breadth, of their virus neutralizing capacity. |
format | Online Article Text |
id | pubmed-9181698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91816982022-06-10 Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein Weißenborn, Lucas Richel, Elie Hüseman, Helena Welzer, Julia Beck, Silvan Schäfer, Simon Sticht, Heinrich Überla, Klaus Eichler, Jutta Int J Mol Sci Article Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide. Furthermore, the proteolytic stability of the cyclic peptide was substantially improved, rendering it a better potential candidate for SARS-CoV-2 therapy. In a more mechanistic approach, the peptides also served as tools to dissect the role of individual mutations in the RBD for the susceptibility of the resulting virus variants to neutralization by the peptides. As the peptides reported here were generated through chemical synthesis, rather than recombinant protein expression, they are amenable to further chemical modification, including the incorporation of a wide range of non-proteinogenic amino acids, with the aim to further stabilize the peptides against proteolytic degradation, as well as to improve the strength, as well the breadth, of their virus neutralizing capacity. MDPI 2022-06-04 /pmc/articles/PMC9181698/ /pubmed/35682988 http://dx.doi.org/10.3390/ijms23116309 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Weißenborn, Lucas Richel, Elie Hüseman, Helena Welzer, Julia Beck, Silvan Schäfer, Simon Sticht, Heinrich Überla, Klaus Eichler, Jutta Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title | Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title_full | Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title_fullStr | Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title_full_unstemmed | Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title_short | Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein |
title_sort | smaller, stronger, more stable: peptide variants of a sars-cov-2 neutralizing miniprotein |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181698/ https://www.ncbi.nlm.nih.gov/pubmed/35682988 http://dx.doi.org/10.3390/ijms23116309 |
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