Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling

• Published in: Angewandte Chemie 2015-07, Vol.127 (30), p.8789-8792
• Main Authors: Assem, Naila, Ferreira, David J., Wolan, Dennis W., Dawson, Philip E.
• Format: Article
• Language: eng ; ger
• Subjects: Biokonjugation; Bridges (structures); Chains; Chemistry; Constraints; Helical; Macrocyclic compounds; Makrocyclisierung; Molecular structure; Oximes; Oximligation; Peptide; Peptides; Proteinmarkierung; Tags
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201502607

Macrocyclization is a broadly applied approach for overcoming the intrinsically disordered nature of linear peptides. Herein, it is shown that dichloroacetone (DCA) enhances helical secondary structures when introduced between peptide nucleophiles, such as thiols, to yield an acetone‐linked bridge (ACE). Aside from stabilizing helical structures, the ketone moiety embedded in the linker can be modified with diverse molecular tags by oxime ligation. Insights into the structure of the tether were obtained through co‐crystallization of a constrained S‐peptide in complex with RNAse S. The scope of the acetone‐linked peptides was further explored through the generation of N‐terminus to side chain macrocycles and a new approach for generating fused macrocycles (bicycles). Together, these studies suggest that acetone linking is generally applicable to peptide macrocycles with a specific utility in the synthesis of stabilized helices that incorporate functional tags. Makrocyclisierungen werden häufig eingesetzt, um die intrinsische Unordnung in linearen Peptiden zu beseitigen. Wird Dichloraceton (DCA) mit Peptid‐Nukleophilen wie z. B. Thiolen umgesetzt, verstärkt es die helikale Sekundärstruktur durch die Bildung einer Aceton‐Brücke. Dieses Keton kann mit unterschiedlichen molekularen Tags durch Oximligation modifiziert werden.