Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan

Peng Wang, Jiang Liu, Xiaomei Zhu, Kenry, Zhengqing Yan, Jiahui Yan, Jitong Jiang, Manlin Fu, Jingyan Ge, Qing Zhu () and Yuguo Zheng
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Peng Wang: Zhejiang University of Technology
Jiang Liu: Zhejiang University of Technology
Xiaomei Zhu: Zhejiang University of Technology
Kenry: Harvard University
Zhengqing Yan: Zhejiang University of Technology
Jiahui Yan: Zhejiang University of Technology
Jitong Jiang: Zhejiang University of Technology
Manlin Fu: Zhejiang University of Technology
Jingyan Ge: Zhejiang University of Technology
Qing Zhu: Zhejiang University of Technology
Yuguo Zheng: Zhejiang University of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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-αvβ3 overexpressed cancer cell lines. The proposed strategy for rapid preparation of stapled peptides would be a robust tool for creating peptide-drug conjugates.

Date: 2023
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DOI: 10.1038/s41467-023-39703-y

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