LAUSR

Peptides provide an attractive modality for targeting challenging drug targets such as intracellular protein-protein interactions. Unfortunately, peptides are generally impermeable to the cell membrane and inherently susceptible to proteolytic degradation in vivo. Macrocyclization of peptides greatly increases their proteolytic stability and in some cases the cell-penetrating activity. Conjugation of peptidyl cargoes to cyclic cell-penetrating peptides has resulted in potent, cell-permeable, and metabolically stable macrocyclic peptides against intracellular protein targets. Proper conjugation/integration of a peptidyl cargo with a cyclic cell-penetrating peptide is critical to retain the activity of each component and generate a biologically active macrocyclic peptide. This chapter describes the different conjugation strategies that have been developed (including endocyclic, bicyclic, and reversible cyclization methods) and the detailed protocols for their preparation.