title: Template-constrained macrocyclic peptides prepared from native, unprotected precursors.
abstract: Peptide-protein interactions are important mediators of cellular-signaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095.
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: Lawson
authors.forename: Tristan E
authors.initials: TE
authors.lastname: Rose
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Harran
mesh_terms: D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D010165:Palladium
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