title: Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling.
abstract: 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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA (USA).
authors.forename: Naila
authors.initials: N
authors.lastname: Assem
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA (USA).
authors.forename: David J
authors.initials: DJ
authors.lastname: Ferreira
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA (USA).
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wolan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA (USA). dawson@scripps.edu.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Dawson
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives* / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D003500:Cyclization; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry; D017433:Protein Structure, Secondary; D012260:Ribonucleases / Q000737:chemistry
chemical_list: D047028:Macrocyclic Compounds; D010455:Peptides; D010456:Peptides, Cyclic; D000096:Acetone; D012260:Ribonucleases; C022542:ribonuclease S; C051717:1,1-dichloroacetone
keywords: bioconjugation; macrocyclization; oxime ligation; peptides; protein labeling