Department of Chemistry, Boston College, Merkert Chemistry Center, 2609 Beacon Street, Chestnut Hill, MA 02467, USA.
Angew Chem Int Ed Engl. 2023 Aug 1;62(31):e202306813. doi: 10.1002/anie.202306813. Epub 2023 Jun 23.
Efficient and site-specific modification of native peptides and proteins is desirable for synthesizing antibody-drug conjugates as well as for constructing chemically modified peptide libraries using genetically encoded platforms such as phage display. In particular, there is much interest in efficient multicyclization of native peptides due to the appeals of multicyclic peptides as therapeutics. However, conventional approaches for multicyclic peptide synthesis require orthogonal protecting groups or non-proteinogenic clickable handles. Herein, we report a cysteine-directed proximity-driven strategy for the constructing bicyclic peptides from simple natural peptide precursors. This linear to bicycle transformation initiates with rapid cysteine labeling, which then triggers proximity-driven amine-selective cyclization. This bicyclization proceeds rapidly under physiologic conditions, yielding bicyclic peptides with a Cys-Lys-Cys, Lys-Cys-Lys or N-terminus-Cys-Cys stapling pattern. We demonstrate the utility and power of this strategy by constructing bicyclic peptides fused to proteins as well as to the M13 phage, paving the way to phage display of novel bicyclic peptide libraries.
高效且定点修饰天然肽和蛋白质对于合成抗体药物偶联物以及使用噬菌体展示等基因编码平台构建化学修饰的肽库是非常理想的。特别是，由于多环肽作为治疗剂的吸引力，人们对高效的天然肽多环化非常感兴趣。然而，多环肽合成的传统方法需要正交保护基团或非天然的点击反应性接头。在此，我们报告了一种半胱氨酸定向的邻近驱动策略，用于从简单的天然肽前体构建双环肽。这种从线性到双环的转变首先是快速的半胱氨酸标记，然后触发邻近驱动的胺选择性环化。这种双环化在生理条件下迅速进行，得到具有 Cys-Lys-Cys、Lys-Cys-Lys 或 N-末端-Cys-Cys 键合模式的双环肽。我们通过构建融合到蛋白质以及 M13 噬菌体上的双环肽来证明该策略的实用性和有效性，为新型双环肽文库的噬菌体展示铺平了道路。
