Non-symmetric stapling of native peptides

Stapling has emerged as a powerful technique in peptide chemistry. It enables precise control over peptide conformation leading to enhanced properties such as improved stability and enhanced binding affinity. Although symmetric stapling methods have been extensively explored, the field of non-symmetric stapling of native peptides has received less attention, largely as a result of the formidable challenges it poses - in particular the complexities involved in achieving the high chemo-selectivity and site-selectivity required to simultaneously modify distinct proteinogenic residues. Over the past 5 years, there have been significant breakthroughs in addressing these challenges. In this Review, we describe the latest strategies for non-symmetric stapling of native peptides, elucidating the protocols, reaction mechanisms and underlying design principles. We also discuss current challenges and opportunities this field offers for future applications, such as ligand discovery and peptide-based therapeutics. Peptide stapling is a powerful technique used to lock peptide conformations and modulate peptide functions. This Review highlights the newest development in non-symmetric stapling of native peptides bearing natural amino acids, elucidating current advances, challenges and future opportunities. Peptide conformation has a crucial role for its functions.Non-symmetric stapling of native peptides constrains peptide conformation by covalently crosslinking two different natural residue side chains within peptides.Non-symmetric stapling can be achieved with high chemo-selectivity and site-selectivity through directing strategy or cooperative strategy.Non-symmetric stapling of native peptides holds great potential for peptide-based therapeutics.The field of non-symmetric stapling of native peptides is still in its early stages with many opportunities for improvement.