Peptide-Directed Ligand Design Enables Chemical Disruption of the Nrf2/MafG Coiled-Coil Transcription Factor Complex.
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220454537