ACE-linked peptides: a convergent approach for peptide macrocyclization and labeling

• Published in: Angewandte Chemie International Edition 2015-06, Vol.54 (30), p.8665-8668
• Main Authors: Assem, Naila, Ferreira, David J., Wolan, Dennis W., Dawson, Philip E.
• Format: Article
• Language: English
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201502607

Macrocyclization is a broadly applied approach for overcoming the intrinsically disordered nature of linear peptides. For example, significant efforts have been developed to stabilize α-helical structures, through tethering proximal side chains. While these approaches successfully mimic protein α-helices, the structural requirements of the tether typically prevent further synthetic modifications to the non-binding face of the helix. Here we demonstrate the utility of dichloroacetone (DCA) to enhance helical secondary structure when introduced between peptide nucleophiles, such as thiols, to yield an acetone (ACE)-linked bridge. In addition to stabilizing helical structures, the ketone moiety embedded into the linker can be modified using oxime ligation with diverse molecular tags. 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 ACE-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 ACE-linking is generally applicable to peptide macrocycles with a specific utility in the synthesis of stabilized helices that incorporate functional tags.