Interchain doubly-bridged α-helical peptides for the development of protein binders

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英文篇名：Interchain doubly-bridged α-helical peptides for the development of protein binders 作者：Yaqi ; Chen ; Jingjing ; Liang ; Tao ; Li ; Ping ; Lin ; Yibing ; Zhao ; Chuanliu ; Wu 英文作者：Yaqi Chen;Jingjing Liang;Tao Li;Ping Lin;Yibing Zhao;Chuanliu Wu;Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University; 英文关键词：Peptides;;α-Helices;;Protein binders;;Bisthioether crosslinkers;;MDM2-p53 interactions 中文刊名：FXKB 英文刊名：中国化学快报(英文版) 机构：Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University; 出版日期：2019-04-15 出版单位：Chinese Chemical Letters 年：2019 期：v.30 基金：financial support from the National Natural Science Foundation of China (Nos. 21675132 and 21822404);; the Program for Changjiang Scholars and Innovative Research Team in University (No. 13036);; the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (No. 21521004) 语种：英文; 页：FXKB201904021 页数：5 CN：04 ISSN：11-2710/O6 分类号：126-130

摘要

Constrained peptide scaffolds that are tolerant to extensive sequence manipulation and amenable to bioactive peptide design are of great value to the development of novel protein binders and peptide therapeutics. In this work, we reported strategies for the design and synthesis of a kind of novel interchain doubly-bridged α-helical peptides, involving mutual stabilization of two peptide α-helices linked by two interchain bisthioether crosslinkers. By taking a MDM2-binding peptide with an α-helical tendency as a model, we demonstrated that α-helical dimers with significantly improved structural and proteolytic stability and nanomolar binding affinity to the target protein can be obtained. By modulating the surface charges on the dimeric peptides, we also obtained a dimeric peptide with enhanced cellpenetrating capability, which can efficiently penetrate into cancer cells and inhibit the intracellular MDM2-p53 interactions to promote cell apoptosis. Considering that many proteins take a surface α-helical segment as the binding motif to mediate their interactions with other proteins, we believe that our interchain doubly-bridged α-helical peptides would provide a promising scaffold for the development of novel high-affinity protein binders.
        Constrained peptide scaffolds that are tolerant to extensive sequence manipulation and amenable to bioactive peptide design are of great value to the development of novel protein binders and peptide therapeutics. In this work, we reported strategies for the design and synthesis of a kind of novel interchain doubly-bridged α-helical peptides, involving mutual stabilization of two peptide α-helices linked by two interchain bisthioether crosslinkers. By taking a MDM2-binding peptide with an α-helical tendency as a model, we demonstrated that α-helical dimers with significantly improved structural and proteolytic stability and nanomolar binding affinity to the target protein can be obtained. By modulating the surface charges on the dimeric peptides, we also obtained a dimeric peptide with enhanced cellpenetrating capability, which can efficiently penetrate into cancer cells and inhibit the intracellular MDM2-p53 interactions to promote cell apoptosis. Considering that many proteins take a surface α-helical segment as the binding motif to mediate their interactions with other proteins, we believe that our interchain doubly-bridged α-helical peptides would provide a promising scaffold for the development of novel high-affinity protein binders.

引文

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