Design and synthesis of Nrf2-derived hydrocarbon stapled peptides for the disruption of protein-DNA-interactions

Misregulation and mutations of the transcription factor Nrf2 are involved in the development of a variety of human diseases. In this study, we employed the technology of stapled peptides to address a protein-DNA-complex and designed a set of Nrf2-based derivatives. Varying the length and position of...

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Published in:PloS one 2022-06, Vol.17 (6), p.e0267651-e0267651
Main Authors: Wiedemann, Bianca, Kamps, Dominic, Depta, Laura, Weisner, Jörn, Cvetreznik, Jana, Tomassi, Stefano, Gentz, Sascha, Hoffmann, Jan-Erik, Müller, Matthias P, Koch, Oliver, Dehmelt, Leif, Rauh, Daniel
Format: Article
Language:English
Subjects:
Amino acids
Analysis
Biology and Life Sciences
Deoxyribonucleic acid
DNA
DNA binding proteins
Genetic transcription
Hydrocarbons
Mutation
Oxidative stress
Peptides
Permeability
Physical Sciences
Proteins
Research and Analysis Methods
Transcription factors
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Summary:Misregulation and mutations of the transcription factor Nrf2 are involved in the development of a variety of human diseases. In this study, we employed the technology of stapled peptides to address a protein-DNA-complex and designed a set of Nrf2-based derivatives. Varying the length and position of the hydrocarbon staple, we chose the best peptide for further evaluation in both fixed and living cells. Peptide 4 revealed significant enrichment within the nucleus compared to its linear counterpart 5, indicating potent binding to DNA. Our studies suggest that these molecules offer an interesting strategy to target activated Nrf2 in cancer cells.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0267651