title: Structural development of stabilized helical peptides as inhibitors of estrogen receptor (ER)-mediated transcription.
abstract: Three types of stabilized helical peptides containing disulfide bonds, C-C cross-linked side chains, or α,α-disubstituted amino acids (2-aminoisobutyric acid (Aib)) were designed and synthesized as inhibitors of estrogen receptor (ER)-coactivator interactions. Furthermore, heptaarginine (R7)-conjugated versions of the peptides were prepared, and their effects on ER-mediated transcription were evaluated at the cellular level (in ER-positive T47D cells). Among them, the R7-conjugated peptides 11 and 12 downregulated the mRNA expression of pS2 (an ER-mediated gene whose expression is upregulated by 17β-estradiol) by 95% (at a dose of 10 μM) and 87% (at a dose of 3 μM), respectively.
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan. Electronic address: demizu@nihs.go.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Demizu
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Misawa
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Nagakubo
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Okuhira
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya, Tokyo 158-8501, Japan; Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan. Electronic address: masaaki@nihs.go.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
mesh_terms: D000621:Aminoisobutyric Acids / Q000737:chemistry; D001120:Arginine / Q000737:chemistry; D002942:Circular Dichroism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053766:Presenilin-2 / Q000235:genetics; D011487:Protein Conformation; D060066:Protein Interaction Maps; D055550:Protein Stability; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D000621:Aminoisobutyric Acids; C508861:PSEN2 protein, human; D010455:Peptides; D053766:Presenilin-2; D011960:Receptors, Estrogen; C100049:2-aminoisobutyric acid; D004958:Estradiol; D001120:Arginine
keywords: Estrogen receptor; Helical peptide; Protein–protein interaction; Transcriptional inhibitor