Structure-Based Design and Synthesis of Potent Cyclic Peptides Inhibiting the YAP鈥揟EAD Protein鈥揚rotein Interaction

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• 作者：Zhisen Zhang ; Zhaohu Lin ; Zheng Zhou ; Hong C. Shen ; S. Frank Yan ; Alexander V. Mayweg ; Zhiheng Xu ; Ning Qin ; Jason C. Wong ; Zhenshan Zhang ; Yiping Rong ; David C. Fry ; Taishan Hu
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：5
• 期：9
• 页码：993-998
• 全文大小：302K
• ISSN：1948-5875

文摘

The YAP鈥揟EAD protein鈥損rotein interaction (PPI) mediates the oncogenic function of YAP, and inhibitors of this PPI have potential usage in treatment of YAP-involved cancers. Here we report the design and synthesis of potent cyclic peptide inhibitors of the YAP鈥揟EAD interaction. A truncation study of YAP interface 3 peptide identified YAP^84鈥?00 as a weak peptide inhibitor (IC₅₀ = 37 渭M), and an alanine scan revealed a beneficial mutation, D94A. Subsequent replacement of a native cation鈭捪€ interaction with an optimized disulfide bridge for conformational constraint and synergistic effect between macrocyclization and modification at positions 91 and 93 greatly boosted inhibitory activity. Peptide 17 was identified with an IC₅₀ of 25 nM, and the binding affinity (K_d = 15 nM) of this 17mer peptide to TEAD1 proved to be stronger than YAP^50鈥?71 (K_d = 40 nM).

Keywords:

Peptide inhibitor; conformational constraint; YAP; TEAD; protein鈭抪rotein interaction