Chemical Engineering of Artificial Transcription Factors by Orthogonal Palladium(II)-Mediated S-Arylation Reactions.

Autor: Lin X; School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 69978, Israel., Harel O; School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 69978, Israel., Jbara M; School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Jan 25; Vol. 63 (5), pp. e202317511. Date of Electronic Publication: 2023 Dec 22.
DOI: 10.1002/anie.202317511
Abstrakt: Site-selective functionalization strategies are in high demand to prepare well-defined homogeneous proteins for basic research and biomedical applications. In this regard, cysteine-based reactions have enabled a broad set of transformations to produce modified proteins for various applications. However, these approaches were mainly employed to modify a single reactive site with a specific transformation. Achieving site selectivity or multiple transformations, essential for preparing complex biomolecules, remains challenging. Herein we demonstrate the power of combining palladium(II)-mediated C-S bond formation and C-S bond cleavage reactions to selectively edit desired cysteine sites in complex and uniquely modified proteins. We developed an orthogonal palladium(II) strategy for rapid and effective diversification of multiple cysteine sites (3-6 residues) with various transformations. Importantly, we employed our approach to prepare 10 complex analogues, including modified, stapled, and multimeric proteins on a milligram scale. Furthermore, we also synthesized a focused library of stabilized artificial transcription factors that displayed enhanced stability and potent DNA binding activity. Our approach enables rapid and effective protein editing and opens new avenues to engineer new biomolecules for fundamental research and therapeutic applications.
(© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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