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

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dc.contributor.authorStieger, Christian E.
dc.contributor.authorPark, Yerin
dc.contributor.authorde Geus, Mark A. R.
dc.contributor.authorKim, Dongju
dc.contributor.authorHuhn, Christiane
dc.contributor.authorSlenczka, J. Sophia
dc.contributor.authorOchtrop, Philipp
dc.contributor.authorMüchler, Judith M.
dc.contributor.authorSüssmuth, Roderich D.
dc.contributor.authorBroichhagen, Johannes
dc.contributor.authorBaik, Mu‐Hyun
dc.contributor.authorHackenberger, Christian P. R.
dc.date.accessioned2022-12-15T12:33:10Z
dc.date.available2022-12-15T12:33:10Z
dc.date.issued2022-08-22
dc.date.updated2022-11-22T17:17:16Z
dc.description.abstractWe 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 CuI‐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.en
dc.description.sponsorshipDFG, 198742546, SPP 1623: Chemoselektive Reaktionen für die Synthese und Anwendung funktionaler Proteine
dc.description.sponsorshipDFG, 392923329, GRK 2473: Bioaktive Peptide - Innovative Aspekte zur Synthese und Biosynthese
dc.identifier.eissn1521-3773
dc.identifier.issn1433-7851
dc.identifier.urihttps://depositonce.tu-berlin.de/handle/11303/17817
dc.identifier.urihttps://doi.org/10.14279/depositonce-16606
dc.language.isoen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc540 Chemie und zugeordnete Wissenschaftende
dc.subject.otherantibody-drug-conjugatesen
dc.subject.otherbioconjugationen
dc.subject.othercysteine profilingen
dc.subject.otherprotein-based electrophilesen
dc.subject.otherprotein–protein conjugationen
dc.titleDFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profilingen
dc.typeArticle
dc.type.versionpublishedVersion
dcterms.bibliographicCitation.articlenumbere202205348
dcterms.bibliographicCitation.doi10.1002/anie.202205348
dcterms.bibliographicCitation.issue41
dcterms.bibliographicCitation.journaltitleAngewandte Chemie International Editionen
dcterms.bibliographicCitation.originalpublishernameWiley
dcterms.bibliographicCitation.originalpublisherplaceNew York, NY
dcterms.bibliographicCitation.volume61
tub.accessrights.dnbfree
tub.affiliationFak. 2 Mathematik und Naturwissenschaften::Inst. Chemie::FG Organische Chemie
tub.publisher.universityorinstitutionTechnische Universität Berlin

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