Design, synthesis and structure-activity relationship study of APC/Asef inhibitors / 上海交通大学学报（医学版）

ABSTRACT

Objective: To design and synthesize APC/Asef peptide inhibitors and investigate the structure-activity relationship between peptides inhibitors and APC protein for exploring better inhibitors. Methods: Based on the best-class inhibitor we had found before-MAI-400, eleven peptide inhibitors were designed, which included the changes of N-terminal capping group, the first amino acid Ala, the fifth amino acid Leu and the last amino acid Glu. According to the results of fluorescence polarization activity detection system and molecular docking, the structure-activity relationship of peptide inhibitors was investigated. Results: Among the eleven peptides, MPI-11 had the highest affinity, whose half maximal inhibitory concentration (IC50) was 0.973 1 mmol/L. The capping group of peptide N-terminal with tert-butoxycarbonyl group reduced the activity slightly. The substitution of the Ala caused different results, changing into Trp, His and Thr definitely reduced the activity but the substitution by Tyr or Phe did not influence the activity too much. And introducing benzene ring into the side chain of Leu had few effects on activity improving. The substitution of side chain carboxyl for amide at the C-terminal glutamate had little effect on the activity. Conclusion: Among the eleven peptides, the capping group of peptide N-terminal cannot be substituted into small groups and Ala cannot be substituted into other amino acids.