As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide‐based drug candidates, drawing upon series of examples to illustrate each strategy.

中文翻译：

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药物发现的金矿：将环肽开发成疗法的策略。

作为一种通用的治疗方法，肽因其强大的结合亲和力，低毒性和靶向传统“不可吸收”的蛋白质表面的能力而备受关注。然而，细胞通透性和代谢稳定性的不足总是限制了体外生物活性肽作为候选药物的成功。肽大环化是克服这些局限性最成熟的策略之一。在过去的几十年中，临床上已经批准了40多种环肽药物，其中绝大多数来自天然产物。在合理设计和体外进化的基础上从头发现的环肽还使得能够与自然界无法提供解决方案的靶标结合。