Peking University, May 12, 2016: Regulatory protein - protein interactions (PPIs are) is an important direction of disease therapeutic target, and the polypeptide by chemical means to stabilize into a fixed conformation is a representative regulatory compounds of PPI. Although in the past ten years, representative scientists such as professor Verdine from Harvard University, professor Arora from New York University etc. have made a very in-depth study of stabilized peptide. However, how the secondary conformation of stabilized polypeptides affect their biophysical properties has not been given a clear explanation and the most critical question is unable to obtain the same chemical composition but different secondary conformation peptides for study.
Li zigang Group at Peking University Shenzhen Graduate School, pioneered the novel concept of "chirality induced helicity" (CIH) strategy to stabilize polypeptide secondary structure. Studies have shown that, by introducing a precise positioned chiral center in the tether of the stabilized polypeptide, and when the absolute configuration of the chiral center is R can be decisive regulatory polypeptide secondary structure. By studying the two enantiomers of CIH, which have exactly the same amino acid sequence but significantly difference in secondary conformation, they found that increasing polypeptide helicity can significantly enhance the stability of the polypeptide.
Further studies showed that for peptides with consensus amino acid sequence, increasing its helicity can significantly increase the cell permeability and target binding affinity. They also found that the newly introduced chiral center substituent groups will interact with the hydrophobic region surrounding the protein binding pocket. This provides a guideline for "fragment-based" polypeptide drug design. The related results were published in the famous magazine Angewandte Chemie. The link is as below: http://onlinelibrary.wiley.com/doi/10.1002/anie.201602806/full. （2016，DOI: 10.1002/anie.201602806R1 ）
The work was done by the guidance of the associate professor Li zigang. The first author is a fourth year graduate student Hu Kuan. Geng Hao, Zhang Qingzhou etc. have made an important contribution for the successful completion of the work. Professor Wu Yundong performed molecular dynamics simulations of this system, which provides a solid theoretical support for the conception of CIH strategy to stabilize peptide’s secondary structure. Associate professor Wang Tao from South China University of Technology, solved the peptide crystal structure and helped to determine the absolute configuration of the chiral center. Professors Wu and Wang are the co-corresponding author of this article.
The work has been supported by the National Natural Science Foundation of China, the Shenzhen municipal innovation fund and the Shenzhen peacock project. Currently the biological application of this strategy has made important progress.
Edited by: Zhang Jiang
Source: Shenzhen Graduate School
