Structural development of stabilized helical peptides as inhibitors of estrogen receptor (ER)-mediated transcription

Bioorg Med Chem. 2015 Aug 1;23(15):4132-4138. doi: 10.1016/j.bmc.2015.06.067. Epub 2015 Jul 2.

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.

Keywords: Estrogen receptor; Helical peptide; Protein–protein interaction; Transcriptional inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoisobutyric Acids / chemistry
  • Arginine / chemistry
  • Circular Dichroism
  • Drug Evaluation, Preclinical / methods
  • Estradiol / pharmacology
  • Humans
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Presenilin-2 / genetics
  • Protein Conformation
  • Protein Interaction Maps
  • Protein Stability
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Solid-Phase Synthesis Techniques
  • Structure-Activity Relationship
  • Transcription, Genetic

Substances

  • Aminoisobutyric Acids
  • PSEN2 protein, human
  • Peptides
  • Presenilin-2
  • Receptors, Estrogen
  • 2-aminoisobutyric acid
  • Estradiol
  • Arginine