›› 2019, Vol. 39 ›› Issue (7): 692-.doi: 10.3969/j.issn.1674-8115.2019.07.002

• Original article (Basic research) • Previous Articles     Next Articles

Design, synthesis and structure-activity relationship study of APC/Asef inhibitors

RUAN Cong1, ZHONG Jie2, YANG Xiu-yan2, ZHANG Jian2   

  1. 1. Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China; 2. Department of Pathophysiology, Shanghai Jiao Tong University College of Basic Medical Sciences; Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai 200025, China
  • Online:2019-07-28 Published:2019-08-26
  • Supported by:
    National Program on Key Basic Research of China (973 Program), 2015CB910403

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 substitutionTyr 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.

Key words: adenomatous polyposis coli (APC), Asef, peptide inhibitor, optimization, structure-activity relationship

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