The synthesis and study of side‐chain lactam‐bridged peptides

Abstract

Side‐chain lactam bridges linking amino acid residues that are spaced several residues apart in the linear sequence offer a convenient and flexible method for introducing conformational constraints into a peptide structure. The availability of a variety of selectively cleavable protecting groups for amines and carboxylic acids allows for several approaches to the synthesis of monocyclic, dicyclic, and bicyclic lactam‐bridged peptides by solid‐phase methods. Multicyclic structures are also accessible, but segment‐condensation syntheses with solution‐phase cyclizations are most likely to provide the best synthetic approach to these more complex constrained peptides. Lactam bridges linking (i, i + 3)‐, (i, i + 4), and (i, i + 7)‐spaced residue pairs have all proven useful for stabilization of α helices, and (i, i + 3)‐linked residues have also been demonstrated to stabilize β‐turns. These structures are finding an increasing number of applications in protein biology, including studies of protein folding, protein aggregation, peptide ligand–receptor recognition, and the development of more potent peptide therapeutics. Defining the functional roles of the amphiphilic α‐helices in medium‐sized peptide hormones, and studying helix propagation from rigid, α‐helix initiating bicyclic peptides are among the most exciting developments currently underway in this field. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 49–75, 2002