A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway,Chemical Science

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A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway
Chemical Science ( IF 7.6 ) Pub Date : 2017-08-29 00:00:00 , DOI: 10.1039/c7sc02420g
Ye Wu _{1,

1,

2,

3,

4} , Ye-Hua Li _{4,

5,

6,

7} , Xiang Li _{1,

2,

3,

4} , Yan Zou _{1,

2,

3,

4} , Hong-Li Liao _{1,

4,

8,

9} , Lei Liu _{4,

5,

6,

7} , Ye-Guang Chen _{4,

5,

6,

7} , Donald Bierer _{10,

11,

12,

13} , Hong-Gang Hu _{1,

2,

3,

4}

Affiliation

The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a β-catenin-binding domain of Axin (469–482) and develop a new category of stapled peptides with the retention of the native side chains. These stapled peptides exhibit high α-helicity, strong proteolytic stability and good cell permeability. Biochemical experiments demonstrate that these stapled peptides can activate β-catenin more efficiently than canonical stapled peptides due to the presence of extra side chains. We expect that the new side-chain-retention stapling method would expand the scope of the all-hydrocarbon stapled peptide strategy by retaining some important peripheral residues for protein–protein interactions or preserving key hydrophilic side chains to improve solubility.

中文翻译：

一种新颖的肽钉策略可保留Wnt /β-catenin信号通路的闭环氨基酸侧链

全碳氢化合物肽的装订策略最近在药物发现中得到了广泛的探索。关于氨基酸侧链在钉合位置的保留，仍存在改进的潜力。在这里，我们描述了一系列新氨基酸，它们不仅包含天然侧链，而且还带有闭环装订化学所需的烯基臂。我们将新氨基酸整合到Axin的β-catenin结合域（469–482）中，并开发了具有天然侧链保留功能的新型固定肽。这些钉合肽表现出高α-螺旋性，强蛋白水解稳定性和良好的细胞渗透性。生化实验表明，由于存在额外的侧链，这些固定肽可以比标准固定肽更有效地激活β-catenin。我们希望新的侧链保留装订方法将通过保留一些重要的周边残基来保持蛋白质间相互作用，或保留关键的亲水性侧链以提高溶解度，从而扩大全烃固定肽策略的范围。

更新日期：2017-09-14

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