In Vitro Selection of Foldamer-Like Macrocyclic Peptides Containing 2-Aminobenzoic Acid and 3-Aminothiophene-2-Carboxylic Acid
In Vitro Selection of Foldamer-Like Macrocyclic Peptides Containing 2-Aminobenzoic Acid and 3-Aminothiophene-2-Carboxylic Acid
复制标题
DOI：
10.1021/jacs.1c12133
复制
发表时间：
2022-02-09
影响因子：
15
通讯作者：
Suga, Hiroaki
中科院分区：
文献类型：
--
作者：
Katoh, Takayuki;Suga, Hiroaki
芳香环-(2,3)-氨基酸（c - AAs），如2-氨基苯甲酸和3-氨基噻吩-2-羧酸，是可以诱导肽独特折叠倾向的基础。尽管由于它们的氨基亲核性较低，它们的核糖体延伸一直是一个艰巨的任务，但我们最近通过工程tRNA（Pro1E2）克服了这个问题，提高了它们在新生肽链中的结合效率。在这里，我们报道了一个含有芳香和脂肪族c β α α的随机大环肽库的核糖体合成，并将其应用于作为模型靶点的针对人类IFNGR1和FXIIa的结合物的新发现。强效结合肽在人血清中不仅具有较高的抑制活性，而且具有较高的蛋白酶抗性。此外，这些c β AAs在展示其性质方面发挥了关键作用，为包含此类独特构建块的全新文件夹状大环建立了发现平台。
Aromatic cyclic beta(2,3)-amino acids (c beta AAs), such as 2-aminobenzoic acid and 3-aminothiophene-2-carboxylic acid, are building blocks that can induce unique folding propensities of peptides. Although their ribosomal elongation had been a formidable task due to the low nucleophilicity of their amino groups, we have recently overcome this issue by means of an engineered tRNA(Pro1E2) that enhances their incorporation efficiency into nascent peptide chains. Here we report ribosomal synthesis of a random macrocyclic peptide library containing aromatic and aliphatic c beta AAs, and its application to de novo discovery of binders against human IFNGR1 and FXIIa as model targets. The potent binding peptides showed not only high inhibitory activity but also high protease resistance in human serum. Moreover, these c beta AAs play a critical role in exhibiting their properties, establishing a discovery platform for de novo foldamer-like macrocycles containing such unique building blocks.