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Title: Designer interface peptide grafts target estrogen receptor alpha dimerization

Abstract

The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Graftedmore » peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable complexes with estrogen receptor in silico. • Inhibitor peptides significantly decrease estrogen induced cell proliferation of ER positive breast cancer cells in vitro.« less

Authors:
 [1];  [2];  [1];  [2]
  1. Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States)
  2. Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States)
Publication Date:
OSTI Identifier:
22606207
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 478; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; DIMERIZATION; DIMERS; DRUGS; ESTROGENS; GRAFTS; IN VITRO; LIGANDS; MAMMARY GLANDS; MOLECULES; NECK; NEOPLASMS; PEPTIDES; RECEPTORS; TRANSCRIPTION FACTORS

Citation Formats

Chakraborty, S., Asare, B.K., Biswas, P.K., E-mail: pbiswas@tougaloo.edu, and Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu. Designer interface peptide grafts target estrogen receptor alpha dimerization. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.07.083.
Chakraborty, S., Asare, B.K., Biswas, P.K., E-mail: pbiswas@tougaloo.edu, & Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu. Designer interface peptide grafts target estrogen receptor alpha dimerization. United States. doi:10.1016/J.BBRC.2016.07.083.
Chakraborty, S., Asare, B.K., Biswas, P.K., E-mail: pbiswas@tougaloo.edu, and Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu. Fri . "Designer interface peptide grafts target estrogen receptor alpha dimerization". United States. doi:10.1016/J.BBRC.2016.07.083.
@article{osti_22606207,
title = {Designer interface peptide grafts target estrogen receptor alpha dimerization},
author = {Chakraborty, S. and Asare, B.K. and Biswas, P.K., E-mail: pbiswas@tougaloo.edu and Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu},
abstractNote = {The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable complexes with estrogen receptor in silico. • Inhibitor peptides significantly decrease estrogen induced cell proliferation of ER positive breast cancer cells in vitro.},
doi = {10.1016/J.BBRC.2016.07.083},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 478,
place = {United States},
year = {Fri Sep 09 00:00:00 EDT 2016},
month = {Fri Sep 09 00:00:00 EDT 2016}
}