Cargando…

DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling

We report the density functional theory (DFT) guided discovery of ethynyl‐triazolyl‐phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using Cu(I)‐catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of f...

Descripción completa

Detalles Bibliográficos
Autores principales: Stieger, Christian E., Park, Yerin, de Geus, Mark A. R., Kim, Dongju, Huhn, Christiane, Slenczka, J. Sophia, Ochtrop, Philipp, Müchler, Judith M., Süssmuth, Roderich D., Broichhagen, Johannes, Baik, Mu‐Hyun, Hackenberger, Christian P. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804898/
https://www.ncbi.nlm.nih.gov/pubmed/35792701
http://dx.doi.org/10.1002/anie.202205348
_version_ 1784862218320347136
author Stieger, Christian E.
Park, Yerin
de Geus, Mark A. R.
Kim, Dongju
Huhn, Christiane
Slenczka, J. Sophia
Ochtrop, Philipp
Müchler, Judith M.
Süssmuth, Roderich D.
Broichhagen, Johannes
Baik, Mu‐Hyun
Hackenberger, Christian P. R.
author_facet Stieger, Christian E.
Park, Yerin
de Geus, Mark A. R.
Kim, Dongju
Huhn, Christiane
Slenczka, J. Sophia
Ochtrop, Philipp
Müchler, Judith M.
Süssmuth, Roderich D.
Broichhagen, Johannes
Baik, Mu‐Hyun
Hackenberger, Christian P. R.
author_sort Stieger, Christian E.
collection PubMed
description We report the density functional theory (DFT) guided discovery of ethynyl‐triazolyl‐phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using Cu(I)‐catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl‐phosphinate. ETP‐reagents were used to obtain fluorescent peptide‐conjugates for receptor labelling on live cells and a stable and a biologically active antibody‐drug‐conjugate. Moreover, we were able to incorporate ETP‐electrophiles into an azide‐containing ubiquitin under native conditions and demonstrate their potential in protein–protein conjugation. Finally, we showcase the excellent cysteine‐selectivity of this new class of electrophile in mass spectrometry based, proteome‐wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules.
format Online
Article
Text
id pubmed-9804898
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-98048982023-01-06 DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling Stieger, Christian E. Park, Yerin de Geus, Mark A. R. Kim, Dongju Huhn, Christiane Slenczka, J. Sophia Ochtrop, Philipp Müchler, Judith M. Süssmuth, Roderich D. Broichhagen, Johannes Baik, Mu‐Hyun Hackenberger, Christian P. R. Angew Chem Int Ed Engl Research Articles We report the density functional theory (DFT) guided discovery of ethynyl‐triazolyl‐phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using Cu(I)‐catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl‐phosphinate. ETP‐reagents were used to obtain fluorescent peptide‐conjugates for receptor labelling on live cells and a stable and a biologically active antibody‐drug‐conjugate. Moreover, we were able to incorporate ETP‐electrophiles into an azide‐containing ubiquitin under native conditions and demonstrate their potential in protein–protein conjugation. Finally, we showcase the excellent cysteine‐selectivity of this new class of electrophile in mass spectrometry based, proteome‐wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules. John Wiley and Sons Inc. 2022-08-22 2022-10-10 /pmc/articles/PMC9804898/ /pubmed/35792701 http://dx.doi.org/10.1002/anie.202205348 Text en © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Stieger, Christian E.
Park, Yerin
de Geus, Mark A. R.
Kim, Dongju
Huhn, Christiane
Slenczka, J. Sophia
Ochtrop, Philipp
Müchler, Judith M.
Süssmuth, Roderich D.
Broichhagen, Johannes
Baik, Mu‐Hyun
Hackenberger, Christian P. R.
DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title_full DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title_fullStr DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title_full_unstemmed DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title_short DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling
title_sort dft‐guided discovery of ethynyl‐triazolyl‐phosphinates as modular electrophiles for chemoselective cysteine bioconjugation and profiling
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804898/
https://www.ncbi.nlm.nih.gov/pubmed/35792701
http://dx.doi.org/10.1002/anie.202205348
work_keys_str_mv AT stiegerchristiane dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT parkyerin dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT degeusmarkar dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT kimdongju dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT huhnchristiane dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT slenczkajsophia dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT ochtropphilipp dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT muchlerjudithm dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT sussmuthroderichd dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT broichhagenjohannes dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT baikmuhyun dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling
AT hackenbergerchristianpr dftguideddiscoveryofethynyltriazolylphosphinatesasmodularelectrophilesforchemoselectivecysteinebioconjugationandprofiling