College of Chemistry, Fuzhou University, Fuzhou, P. R. China.
College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, P. R. China.
Nat Rev Chem. 2024 May;8(5):304-318. doi: 10.1038/s41570-024-00591-5. Epub 2024 Apr 4.
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.
订书钉技术在肽化学中已经崭露头角。它可以精确控制肽的构象，从而提高稳定性和增强结合亲和力等特性。尽管对称订书钉方法已经得到了广泛的探索，但天然肽的非对称订书钉领域受到的关注较少，这主要是因为它带来了巨大的挑战——特别是在实现同时修饰不同的蛋白质残基所需的高化学选择性和位点选择性方面存在复杂性。在过去的 5 年中，在解决这些挑战方面取得了重大突破。在这篇综述中，我们描述了天然肽的非对称订书钉的最新策略，阐明了方案、反应机制和潜在的设计原则。我们还讨论了该领域为未来应用（如配体发现和基于肽的治疗）提供的当前挑战和机遇。
