Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.
Abstract
Transcription factor protein interactions remain among the most challenging targets in chemical biology, particularly those driven by leucine zipper coiled coil assemblies. For this challenge we developed a peptide-directed ligand design strategy identifying inhibitors of the Nrf2/MafG transcription factor complex, a key driver of cytoprotective signalling and cancer chemoresistance. MafG-derived α-helical peptides bind Nrf2 and disrupt formation of the Nrf2/MafG/DNA complex. Guided by structural modelling, peptide-small molecule hybrids were subsequently developed that preserved inhibitory activity while reducing peptide content. Lead hybrids inhibited Nrf2/MafG/DNA assembly, suppressed Nrf2-dependent transcriptional responses, reduced HO-1 and NQO1 gene expression, NQO1 enzymatic activity, and decreased nuclear localisation of Nrf2 in A549 cells. Disruption of Nrf2/MafG signalling restored sensitivity to gemcitabine in an intrinsically chemoresistant lung cancer model. This provides a new approach for the modulation of coiled-coil transcription factor interactions and new chemical probes for Nrf2-dependent chemoresistance in cancer biology.
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BibTeX
@misc{hyde2026peptidedirected,
title = {{Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.}},
author = {Ellen E. Hyde and Emily Hobson and Owen Mullen and Zoë R. Goddard and Sean Tattan and Marco M.D. Cominetti and Mark Searcey and Maria A. O’Connell and Andrew M. Beekman},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009846/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009846/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.
AU - Ellen E. Hyde
AU - Emily Hobson
AU - Owen Mullen
AU - Zoë R. Goddard
AU - Sean Tattan
AU - Marco M.D. Cominetti
AU - Mark Searcey
AU - Maria A. O’Connell
AU - Andrew M. Beekman
PY - 2026
DA - 2026/10/05
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009846/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009846/v1
AB - Transcription factor protein interactions remain among the most challenging targets in chemical biology, particularly those driven by leucine zipper coiled coil assemblies. For this challenge we developed a peptide-directed ligand design strategy identifying inhibitors of the Nrf2/MafG transcription factor complex, a key driver of cytoprotective signalling and cancer chemoresistance. MafG-derived α-helical peptides bind Nrf2 and disrupt formation of the Nrf2/MafG/DNA complex. Guided by structural modelling, peptide-small molecule hybrids were subsequently developed that preserved inhibitory activity while reducing peptide content. Lead hybrids inhibited Nrf2/MafG/DNA assembly, suppressed Nrf2-dependent transcriptional responses, reduced HO-1 and NQO1 gene expression, NQO1 enzymatic activity, and decreased nuclear localisation of Nrf2 in A549 cells. Disruption of Nrf2/MafG signalling restored sensitivity to gemcitabine in an intrinsically chemoresistant lung cancer model. This provides a new approach for the modulation of coiled-coil transcription factor interactions and new chemical probes for Nrf2-dependent chemoresistance in cancer biology.
ER -