Synthesis And Activity Of Macrocyclic Peptide Targeting PP2A Phosphatase

Abnormal protein-protein interaction often causes diseases,such as cancer.Alpha-helix is often encountered in the protein-protein interface.The development of helical conformation-constrained peptide has become an important strategy to interfere with protein-protein interactions.The helical conformation-constrained peptide can be constructed in a variety of ways.Our group have developed a high-efficient and flexible N-terminal helical nucleation strategy for the construction of helical conformation-constrained peptide,which mainly forms by introducing a thioether bond between the N-terminal thiol of the polypeptide and i+3(or i+4,i+7,i+11)position to afford single-turn,double-turn,and three-turn helical conformation-constrained peptide.The goal of my thesis is to use the flexible N-terminal helix-nucleating strategy to develop macrocyclic peptides that regulate the Hippo pathway.The disorder of the Hippo signaling pathway is closely related to the occurrence and development of many cancers.The latest study has promoted the finding of a helical conformation-constrained peptide,SHAP,that can be used to regulate the Hippo pathway.SHAP can disrupt the formation of the PP2 A holoenzyme complex containing STRN3,and reactivates the activity of tumor suppressor in this pathway,thereby inhibiting or killing gastric cancer cells.However,the enzymatic stability and inhibitory activity of SHAP need to be further improved.This study utilized the N-terminal helix nucleation strategy to optimize the structure of the bioactive SHAP,in order to develop a conformationally restricted peptide with enhanced biological activity.Through structural optimization,we found a series of marocyclic peptides with higher helical content,whose enzymatic stability and inhibitory activity have been remarkably improved.More importantly,we have developed a noval bicyclic peptide SHAP-27,which shows much higher inhibitory activity than SHAP in terms of inhibiting cancer cell growth and clone formation,and its enzymatic stability is also much better than SHAP.The study has demostrated the biological applicability of the N-terminal helix-nucleating strategy developed by our group.In summary,this study mainly uses the N-terminal helix nucleation strategy method to optimize the structure of SHAP,to improve the enzymatic stability and biological activity of SHAP.Our study may provide a more promising candidate peptide for targeting the Hippo pathway.