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Structure activity relationships of peptidic analogs of MyoD for the development of Id1 inhibitors as antiproliferative agents
Author(s) -
Hsiao YuCheng,
Yang DeLen,
Hung HuiLing,
Lung FengDi T.
Publication year - 2013
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2549
Subject(s) - peptide , circular dichroism , chemistry , biochemistry , transcription factor , surface plasmon resonance , microbiology and biotechnology , biology , gene , materials science , nanoparticle , nanotechnology
Id proteins, inhibitors of DNA binding proteins, have highly conserved dimerization motif known as the helix‐loop‐helix (HLH) domain that acts as a negative regulator of basic HLH (bHLH) transcription factors. In signaling pathways, Id proteins play an important role in cellular development, proliferation, and differentiation. The mechanism of Id proteins is to antagonize bHLH proteins, thereby preventing them from binding to DNA and inhibiting transcription of cellular differentiation‐associated genes in cancer. Recently, we reported an inhibitor of Id1, peptide 3C, which showed good affinity to Id1 protein and exhibited inhibitory effects in cancer cells. In this study, Ala (A)‐substituted analogs of peptide 3C were synthesized by SPPS, purified by RP‐HPLC, and characterized by MALDI‐TOF MS. Binding of each peptide to Id1 or Id1‐HLH (the HLH domain of Id1) was monitored by surface plasmon resonance (SPR)‐based biosensor. Biological effect of each peptide in MCF‐7 breast cancer cells was analyzed by MTT cell viability assay. The secondary structure of substituted analogs of peptide 3C was investigated by circular dichroism (CD) spectroscopy. SPR results revealed that A‐substituted analogs of peptide 3C showed weaker binding to Id1 than that of peptide 3C, indicating that the six amino acid residues in the N ‐terminal of peptide 3C were all essential for binding to Id1 and the importance of amino acid residue was I 2 > Q 6 > Y 1 > G 4 > L 5 > E 3 . In addition, substitution of E 3 in peptide 3C with D, Q, and R did not improve the binding potency of peptide 3C. MTT assay demonstrated that neither A‐substituted nor position 3‐substituted analogs of peptide 3C showed increased antiproliferative effect in MCF‐7 cancer cells. CD results indicated that peptide 3C exhibited the highest content of α ‐helical structure (39.37%), suggesting that the α ‐helical structure may contribute to its binding potency for Id1 and Id1‐HLH. SAR results provided important information for the development of peptidic inhibitors of Id1 as anticancer agents and demonstrated peptide 3C as a promising lead for further modifications. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.