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

作者：Wu, Ye; Li, Ye-Hua; Li, Xiang; Zou, Yan; Liao, Hong-Li; Liu, Lei; Chen, Ye-Guang^*; Bierer, Donald^*; Hu, Hong-Gang^*

来源：Chemical Science, 2017, 8(11): 7368-7373.

DOI：10.1039/c7sc02420g

• PROTEIN-PROTEIN INTERACTIONS
• ALPHA-HELICAL PEPTIDES
• SOLID-PHASE SYNTHESIS
• HYDROGEN-BOND
• BETA-CATENIN
• INHIBITION
• COMPLEX
• MACROCYCLIZATION
• TRANSCRIPTION
• CONFORMATION

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 beta-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 alpha-helicity, strong proteolytic stability and good cell permeability. Biochemical experiments demonstrate that these stapled peptides can activate beta-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.

• 出版日期2017-11-1
• 单位成都医学院; 中国人民解放军第二军医大学; 清华大学