Peptides are a growing therapeutic class due to their unique spatial characteristics that can target traditionally “undruggable” protein–protein interactions and surfaces. Despite their advantages, peptides must overcome several key shortcomings to be considered as drug leads, including their high conformational flexibility and susceptibility to proteolytic cleavage. As a general approach for overcoming these challenges, macrocyclization of a linear peptide can usually improve these characteristics. Their synthetic accessibility makes peptide macrocycles very attractive, though traditional synthetic methods for macrocyclization can be challenging for peptides, especially for head-to-tail cyclization. This review provides an updated summary of the available macrocyclization chemistries, such as traditional lactam formation, azide–alkyne cycloadditions, ring-closing metathesis as well as unconventional cyclization reactions, and it is structured according to the obtained functional groups. Keeping peptide chemistry and screening in mind, the focus is given to reactions applicable in solution, on solid supports, and compatible with contemporary screening methods.

中文翻译：

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环肽和拟肽的大环化策略

肽是一个不断发展的治疗类别，因为其独特的空间特性可以针对传统上“不可成药”的蛋白质-蛋白质相互作用和表面。尽管肽有其优点，但要被视为先导药物，必须克服几个关键缺点，包括其高构象灵活性和对蛋白水解裂解的敏感性。作为克服这些挑战的通用方法，线性肽的大环化通常可以改善这些特性。它们的合成可及性使得肽大环化合物非常有吸引力，尽管传统的大环化合成方法对于肽来说可能具有挑战性，尤其是头尾环化。本综述提供了现有大环化化学的最新总结，例如传统的内酰胺形成、叠氮-炔环加成、闭环复分解以及非常规环化反应，并根据所获得的官能团进行结构化。牢记肽化学和筛选，重点关注适用于溶液、固体支持物的反应，并与当代筛选方法兼容。