Citation: Chen Yaqi, Liang Jingjing, Li Tao, Lin Ping, Zhao Yibing, Wu Chuanliu. Interchain doubly-bridged α-helical peptides for the development of protein binders[J]. Chinese Chemical Letters, ;2019, 30(4): 924-928. doi: 10.1016/j.cclet.2019.02.013 shu

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

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, Xiamen 361005, China

chlwu@xmu.edu.cn

Received Date: 10 January 2019
Revised Date: 29 January 2019
Accepted Date: 11 February 2019
Available Online: 19 April 2019

Figures(5)

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.
- Peptides,
- α-Helices,
- Protein binders,
- Bisthioether crosslinkers,
- MDM2-p53 interactions
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