Massey Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, 23219, Virginia, USA.
Department of Chemistry, Virginia Commonwealth University, 1001 W Main Street, Richmond, 23284, VA, USA.
Chem Commun (Camb). 2022 Jun 9;58(47):6737-6740. doi: 10.1039/d2cc01148d.
Peptide macrocycles (PMCs) are increasingly popular for the development of inhibitors of protein-protein interactions (PPIs). Large libraries of PMCs are accessible using display technologies like mRNA display and phage display. These technologies require macrocyclization chemistries to be compatible with biological milieu, severely limiting the types of technologies available for cyclization. Here, we introduce the novel non-canonical amino acid (ncAA) -cyanoacetylene-L-Phe (pCAF), which facilitates spontaneous, co-translational cyclization through Michael addition with cysteine under physiological conditions. This new, robust chemistry creates stable macrocycles of a wide variety of ring sizes including bicyclic structures.
肽大环（PMCs）在开发蛋白质-蛋白质相互作用（PPIs）抑制剂方面越来越受欢迎。使用 mRNA 展示和噬菌体展示等显示技术可以获得大量的 PMC 文库。这些技术要求大环化学与生物环境兼容，严重限制了可用于环化的技术类型。在这里，我们引入了新型非天然氨基酸（ncAA）-氰基乙炔-L-苯丙氨酸（pCAF），它在生理条件下通过与半胱氨酸的迈克尔加成促进自发的共翻译环化。这种新的、强大的化学方法可以形成各种大小的稳定大环，包括双环结构。
