Abstract
Protein-protein interactions (PPIs) pose challenges for intervention through small molecule drugs, protein drugs, and linear peptides due to inherent limitations such as inappropriate size, poor stability, and limited membrane penetrance. The emergence of stapled α-helical peptides presents a promising avenue as potential competitors for inhibiting PPIs, demonstrating enhanced structural stability and increased tolerance to proteolytic enzymes. This review aims to provide an overview of metal-free stapling strategies involving two identical natural amino acids, two different natural amino acids, non-natural amino acids, and multicomponent reactions. The primary objective is to delineate comprehensive peptide stapling approaches and foster innovative ideation among readers by accentuating methodologies published within the past five years and elucidating evolving trends in stapled peptides.