›› 2018, Vol. 38 ›› Issue (10): 1139-.doi: 10.3969/j.issn.1674-8115.2018.10.001

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

Structure optimum and biological activity studies of APC/Asef peptide inhibitors

QIAN Jin-xing, ZHANG Jian   

  1. Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China
  • Online:2018-10-28 Published:2018-11-18
  • Supported by:
    National Program on Key Basic Research Project of China (973 Program),2015CB910403

Abstract: Objective · To design and synthesize APC/Asef peptide inhibitors, and investigate the relationship between the structures and affinity of peptides. Methods · Based on crystal structure of the APC-MAI-150 complex, on the one hand, 3-phenylpropane, Glu-Glu (GG) and β-Ala-Ala (β-AA) were used to replace carbobenzoxy (CBZ) at the N terminal of MAI-150 to bind -NH2; on the other hand, -CN, -NO2, -NH2, and -F were replaced the parahydroxyl on the sixth tyrosine (Tyr) side chain benzene at the N terminal of MAI-150. And seven peptides were synthesized. Fluorescence polarization was applied to test peptide affinity, and molecular design laboratory-3 (MDL-3), MDL-4 and MDL-5 were docked into APC protein based on the results of activity. The structure-activity relationship of the three peptides was studiedcombining the binding patterns of computer docked peptide and APC protein. Results · Among the seven peptides, the N terminal 3-phenylpropane linked -NH2 of peptide MDL-5 had the highest affinity, which IC50 was 2.35 μmol/L. Compared with MDL-5, the affinity of MDL-6 and MDL-7 were significantly reduced. The para-hydroxyl on the sixth Tyr side chain benzene at the N terminal replaced with -NH2 (MDL-3) and -F (MDL-4), which the affinity were higher than -CN (MDL-1) and -NO2 (MDL-2). However, the affinity of newly synthesized peptides was lower than MAI-150. Conclusion · Transforming peptide N terminal linked -NH2 and the para-hydroxyl group on the sixth Tyr side chain benzene doesnt help to improve the affinity of peptides.

Key words: APC/Asef, peptide inhibitor, structure-activity relationship

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