Macrocyclization strategies for cyclic peptides and peptidomimetics.
Macrocyclization strategies for cyclic peptides and peptidomimetics.
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DOI：
10.1039/d1md00083g
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发表时间：
2021-08-18
影响因子：
4.1
通讯作者：
Lamers C
中科院分区：
文献类型：
--
作者：
Bechtler C;Lamers C
多肽由于其独特的空间特性，可以靶向传统上“不可药物”的蛋白质-蛋白质相互作用和表面，成为一种日益增长的治疗类。尽管多肽具有优势，但它们必须克服几个关键缺点才能被认为是药物先导，包括它们的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一般方法，线性肽的大环化通常可以改善这些特性。它们的可合成性使得肽大环非常有吸引力，尽管传统的大环化合成方法对肽来说是具有挑战性的，特别是对于头尾环化。本文综述了现有的大环化化学方法，如传统的内酰胺形成、叠氮-炔环加成、合环复合以及非常规的大环化反应，并根据所获得的官能团进行了结构分析。考虑到肽化学和筛选，重点是在溶液中适用的反应，在固体载体上，并与当代筛选方法兼容。头链、尾链或侧链之间的大环化是一种常用的增强肽和拟肽稳定性、选择性和亲和力的策略。
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. Macrocyclization between head, tail or sidechains is a frequently employed strategy to enhance peptide and peptidomimetic stability, selectivity and affinity.
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