Studies on new chemical probes development that assumed dimeric interface of the EGF receptor ectodomain a target

2015 Fiscal Year Final Research Report

• Project/Area Number: 26893061
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Mizuguchi Takaaki 東京医科歯科大学, 生体材料工学研究所, 助教 (30732557)
• Co-Investigator(Renkei-kenkyūsha): TAMAMURA Hirokazu 東京医科歯科大学, 生体材料工学研究所, 教授 (80217182) ; NOMURA Wataru 東京医科歯科大学, 生体材料工学研究所, 准教授 (80463909)
• Research Collaborator: AKAJI Kenichi 京都薬科大学, 薬学部, 教授 (60142296) ; TOYAMA Kei 東京医科歯科大学, 大学院医歯学総合研究科, 大学院生
• Project Period (FY): 2014-08-29 – 2016-03-31
• Keywords: EGFレセプター / 二量化阻害 / 二量体化アーム / 蛍光プローブ / 抗がん活性ペプチド / 細胞内薬物送達分子 / 環状ペプチド / フルオレセイン

Outline of Final Research Achievements

We have developed a cyclic decapeptide 1, which acts on the extracellular region of the EGF receptor, preventing it from dimerizing. Fluorescein-labeled peptide 2 at the N-terminus of peptide 1 was synthesized. Peptide 2 essentially retained the inhibitory activity of peptide 1 against the receptor autophosphorylation. Confocal microscopy studies revealed that in carcinoma cells, the fluorescence of peptide 2 was localized inside some vesicles. Treatment of intact cells by peptide 1 in combination with peptide 2 decreased the fluorescence intensity significantly compared to treatment with only peptide 2. Seven derivatives of peptide 2 were synthesized and used to treat the cells. Peptides 6 and 9 showed the highest fluorescence intensity in cells. These two derivatives were proven to have higher inhibitory activity against the autophosphorylation than peptide 2, which would therefore be a useful delivery peptide and fluorescent probe to find new inhibitors against the EGF receptor.

Free Research Field

創薬化学