Stapled peptides for new drug discovery

Many important biological processes are regulated through protein–protein interactions (PPIs), which are regarded as key mechanisms of various signaling pathways and potential targets for new drug design. Peptide inhibitors have shown promising developments in blocking large surface PPIs. Nevertheless, linear peptides have difficulty maintaining stable secondary structures, which renders them susceptible to degradation by hydrolases and makes it difficult for them to cross cell membranes. The stapled peptide strategy introduces a method of stabilizing the conformation of the peptide via side chain chemical cross-linkage, which improves the helicity, metabolic stability, and cell membrane permeability of the linear peptide and can improve its original target affinity. The stapled peptide strategy has become an important method for structurally modifying peptides. These unique helical conformation-locked scaffolds will inevitably lead to the emergence of new peptide drugs, especially those targeting specific PPIs. Here, we summarize methods for constructing stapled peptides based on different types of chemical reactions including transition metal-catalyzed and acid–amine condensation reactions, click chemistry, and photocatalytic reactions, and their applications in biological applications and drug development.