Media contributions
1Media contributions
Title Targeting the Untouchables: Covalent Peptides That Target Elusive Transcription Factors Media name/outlet The Medicine Maker Date 27/06/25 Description Transcription factors (TFs) are crucial for gene expression but have long been tough drug targets. Peptides, which can bind to broad and shallow protein surfaces, offer a promising way to reach these targets inside cells.
Researchers at the University of Bath, UK, developed a method that found a strong inhibitor of the transcription factor cJun, a protein linked to melanoma and other cancers. They used a large peptide library to find candidates that could bond with a specific cysteine (C269) in cJun’s DNA-binding region.
A key feature of their method was adding a “warhead” — a chemical group that reacts with the target site. In this case, the warhead formed a permanent bond with the cysteine in cJun, creating an irreversible and selective inhibitor. When designed well, such covalent inhibitors can be more powerful and longer-lasting.
To do so, the team swapped a reversible bonding cysteine in a peptide for the synthetic warhead to make the bond permanent. The final product, called HW33, was stronger, more selective, and more effective in cell tests. In melanoma cells, HW33 lowered cJun levels and reduced cell survival, opening the door to similar irreversible inhibitors for other hard-to-target proteins.
We spoke with lead researcher Jody Mason about the difficulties of using this method in live cells and how their peptide library might help find new treatments for tough-to-target proteins like transcription factors.URL https://themedicinemaker.com/issues/2025/articles/jun/targeting-the-untouchables-covalent-peptides-that-target-elusive-transcription-factors/ Persons Jody Mason