Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, MA, 02134, USA.
Nat Commun. 2023 Jul 5;14(1):3973. doi: 10.1038/s41467-023-39703-y.
Cyclic peptides have attracted tremendous attention in the pharmaceutical industry owing to their excellent cell penetrability, stability, thermostability, and drug-like properties. However, the currently available facile methodologies for creating such peptides are rather limited. Herein, we report an efficient and direct peptide cyclization via rhodium(III)-catalyzed C(7)-H maleimidation. Notably, this catalytical system has excellent regioselectivity and high tolerance of functional groups which enable late-stage cyclization of peptides. This architecture of cyclic peptides exhibits higher bioactivity than its parent linear peptides. Moreover, the Trp-substituted maleimide displays excellent reactivity toward Michael addition, indicating its potential as a click functional group for applications in chemical biology and medicinal chemistry. As a proof of principle, RGD-GFLG-DOX, which is a peptide-drug-conjugate, is constructed and it displays a strong binding affinity and high antiproliferative activity toward integrin-αvβ overexpressed cancer cell lines. The proposed strategy for rapid preparation of stapled peptides would be a robust tool for creating peptide-drug conjugates.
环肽由于其出色的细胞穿透性、稳定性、热稳定性和类药性而在制药行业引起了极大的关注。然而，目前可用于生成此类肽的简便方法相当有限。在此，我们报告了一种通过铑(III)催化的 C(7)-H 马来酰亚胺化实现高效且直接的肽环化方法。值得注意的是，该催化体系具有出色的区域选择性和对官能团的高耐受性，可实现肽的后期环化。这种环肽结构表现出比其母体线性肽更高的生物活性。此外，色氨酸取代的马来酰亚胺对迈克尔加成反应表现出优异的反应性，表明其作为点击官能团在化学生物学和药物化学中的潜在应用。作为原理的证明，构建了肽-药物偶联物 RGD-GFLG-DOX，其对整合素-αvβ过表达的癌细胞系表现出强烈的结合亲和力和高抗增殖活性。该快速制备订书肽的策略将成为构建肽-药物偶联物的有力工具。
