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General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins
Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870662/ https://www.ncbi.nlm.nih.gov/pubmed/33558523 http://dx.doi.org/10.1038/s41467-021-21209-0 |
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author | Laps, Shay Atamleh, Fatima Kamnesky, Guy Sun, Hao Brik, Ashraf |
author_facet | Laps, Shay Atamleh, Fatima Kamnesky, Guy Sun, Hao Brik, Ashraf |
author_sort | Laps, Shay |
collection | PubMed |
description | Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery. |
format | Online Article Text |
id | pubmed-7870662 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78706622021-02-11 General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins Laps, Shay Atamleh, Fatima Kamnesky, Guy Sun, Hao Brik, Ashraf Nat Commun Article Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery. Nature Publishing Group UK 2021-02-08 /pmc/articles/PMC7870662/ /pubmed/33558523 http://dx.doi.org/10.1038/s41467-021-21209-0 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Laps, Shay Atamleh, Fatima Kamnesky, Guy Sun, Hao Brik, Ashraf General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title | General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title_full | General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title_fullStr | General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title_full_unstemmed | General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title_short | General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
title_sort | general synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870662/ https://www.ncbi.nlm.nih.gov/pubmed/33558523 http://dx.doi.org/10.1038/s41467-021-21209-0 |
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