Yang Fenfang, Yin Feng, Li Zigang
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, People's Republic of China.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen, People's Republic of China.
Methods Mol Biol. 2022;2371:391-409. doi: 10.1007/978-1-0716-1689-5_21.
Over the past two decades, significant efforts have invested in the development of strategies for the stabilization of macrocyclic peptides with α-helix structure by stapling their architectures. These strategies can be divided into two categories: side chain to side chain cross-linking and N-terminal helix nucleation. These stable macrocyclic peptides have been applied in PPI inhibitors and self-assembly materials. Compared with unmodified short peptides, stable α-helix macrocyclic polypeptides have better biophysical properties including higher serum stability, cell permeability, and higher target affinity. This chapter will systematically introduce approaches for helical stabilization of peptide macrocycles, such as ring-closing metathesis (RCM), lactamisation, cycloadditions, reversible reactions, thioether formation as well as newly found sulfonium center formation and the common use of helical stabilized macrocyclic peptides.
在过去二十年中，人们投入了大量精力来开发通过固定其结构来稳定具有α-螺旋结构的大环肽的策略。这些策略可分为两类：侧链到侧链交联和N端螺旋成核。这些稳定的大环肽已应用于蛋白质-蛋白质相互作用（PPI）抑制剂和自组装材料中。与未修饰的短肽相比，稳定的α-螺旋大环多肽具有更好的生物物理性质，包括更高的血清稳定性、细胞渗透性和更高的靶标亲和力。本章将系统介绍肽大环螺旋稳定化的方法，如闭环复分解反应（RCM）、内酰胺化、环加成反应、可逆反应、硫醚形成以及新发现的锍中心形成，以及螺旋稳定大环肽的常见用途。
