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.

装订已成为肽化学中一项强大的技术。它能够精确控制肽构象，从而增强稳定性和结合亲和力等特性。尽管对称装订方法已被广泛探索，但天然肽的非对称装订领域受到的关注较少，这主要是由于它带来的巨大挑战，特别是实现高化学选择性和位点的复杂性。同时修饰不同蛋白质残基所需的选择性。过去5年，在应对这些挑战方面取得了重大突破。在这篇综述中，我们描述了天然肽非对称缝合的最新策略，阐明了方案、反应机制和基本设计原则。我们还讨论了该领域当前的挑战和为未来应用提供的机遇，例如配体发现和基于肽的治疗。