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A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates

Bioorthogonal chemistry holds great potential to generate difficult‐to‐access protein–protein conjugate architectures. Current applications are hampered by challenging protein expression systems, slow conjugation chemistry, use of undesirable catalysts, or often do not result in quantitative product...

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Autores principales: Baalmann, Mathis, Neises, Laura, Bitsch, Sebastian, Schneider, Hendrik, Deweid, Lukas, Werther, Philipp, Ilkenhans, Nadja, Wolfring, Martin, Ziegler, Michael J., Wilhelm, Jonas, Kolmar, Harald, Wombacher, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496671/
https://www.ncbi.nlm.nih.gov/pubmed/32342666
http://dx.doi.org/10.1002/anie.201915079
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author Baalmann, Mathis
Neises, Laura
Bitsch, Sebastian
Schneider, Hendrik
Deweid, Lukas
Werther, Philipp
Ilkenhans, Nadja
Wolfring, Martin
Ziegler, Michael J.
Wilhelm, Jonas
Kolmar, Harald
Wombacher, Richard
author_facet Baalmann, Mathis
Neises, Laura
Bitsch, Sebastian
Schneider, Hendrik
Deweid, Lukas
Werther, Philipp
Ilkenhans, Nadja
Wolfring, Martin
Ziegler, Michael J.
Wilhelm, Jonas
Kolmar, Harald
Wombacher, Richard
author_sort Baalmann, Mathis
collection PubMed
description Bioorthogonal chemistry holds great potential to generate difficult‐to‐access protein–protein conjugate architectures. Current applications are hampered by challenging protein expression systems, slow conjugation chemistry, use of undesirable catalysts, or often do not result in quantitative product formation. Here we present a highly efficient technology for protein functionalization with commonly used bioorthogonal motifs for Diels–Alder cycloaddition with inverse electron demand (DA(inv)). With the aim of precisely generating branched protein chimeras, we systematically assessed the reactivity, stability and side product formation of various bioorthogonal chemistries directly at the protein level. We demonstrate the efficiency and versatility of our conjugation platform using different functional proteins and the therapeutic antibody trastuzumab. This technology enables fast and routine access to tailored and hitherto inaccessible protein chimeras useful for a variety of scientific disciplines. We expect our work to substantially enhance antibody applications such as immunodetection and protein toxin‐based targeted cancer therapies.
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spelling pubmed-74966712020-09-25 A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates Baalmann, Mathis Neises, Laura Bitsch, Sebastian Schneider, Hendrik Deweid, Lukas Werther, Philipp Ilkenhans, Nadja Wolfring, Martin Ziegler, Michael J. Wilhelm, Jonas Kolmar, Harald Wombacher, Richard Angew Chem Int Ed Engl Research Articles Bioorthogonal chemistry holds great potential to generate difficult‐to‐access protein–protein conjugate architectures. Current applications are hampered by challenging protein expression systems, slow conjugation chemistry, use of undesirable catalysts, or often do not result in quantitative product formation. Here we present a highly efficient technology for protein functionalization with commonly used bioorthogonal motifs for Diels–Alder cycloaddition with inverse electron demand (DA(inv)). With the aim of precisely generating branched protein chimeras, we systematically assessed the reactivity, stability and side product formation of various bioorthogonal chemistries directly at the protein level. We demonstrate the efficiency and versatility of our conjugation platform using different functional proteins and the therapeutic antibody trastuzumab. This technology enables fast and routine access to tailored and hitherto inaccessible protein chimeras useful for a variety of scientific disciplines. We expect our work to substantially enhance antibody applications such as immunodetection and protein toxin‐based targeted cancer therapies. John Wiley and Sons Inc. 2020-05-26 2020-07-27 /pmc/articles/PMC7496671/ /pubmed/32342666 http://dx.doi.org/10.1002/anie.201915079 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Articles
Baalmann, Mathis
Neises, Laura
Bitsch, Sebastian
Schneider, Hendrik
Deweid, Lukas
Werther, Philipp
Ilkenhans, Nadja
Wolfring, Martin
Ziegler, Michael J.
Wilhelm, Jonas
Kolmar, Harald
Wombacher, Richard
A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title_full A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title_fullStr A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title_full_unstemmed A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title_short A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well‐Defined Protein–Protein Conjugates
title_sort bioorthogonal click chemistry toolbox for targeted synthesis of branched and well‐defined protein–protein conjugates
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496671/
https://www.ncbi.nlm.nih.gov/pubmed/32342666
http://dx.doi.org/10.1002/anie.201915079
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