Cracking the “Undruggable” Code:

For decades, certain cancer-driving proteins have been considered essentially off-limits to drug developers. These proteins, called transcription factors, act like master switches in our cells, controlling which genes turn on and off. In cancer, they get stuck in the “on” position, fueling uncontrolled growth. The problem? Their smooth, featureless surfaces give conventional drugs almost nothing to grip onto.

Now, researchers at the University of Bath may have found an elegant way around this long-standing obstacle.

The clever trick: staple them inside bacteria

The Bath team has developed a technology that uses bacteria to build, chemically stabilize, and test millions of potential drug molecules inside living cells, all in one go. The molecules in question are peptides, short chains of amino acids that can be designed to interfere with specific proteins.

The key innovation is the “stapling” step. Each bacterium produces a different peptide, which is then chemically modified inside the living cell, acting like a molecular staple, locking the peptide into a defined shape it would not normally adopt. This rigid shape is what makes the peptide stable and effective enough to work inside a cell.

What makes the approach genuinely clever is that the chemistry happens while the drug is being tested. Only bacteria that produce peptides which are both effective and non-toxic survive, meaning the biological process itself filters out the failures and surfaces the winners naturally.

Faster, greener, and scalable

Beyond its scientific ingenuity, the method also sidesteps many of the practical headaches of conventional drug discovery. Traditional methods require peptides to be made, purified, chemically modified, and purified again — whereas stapled peptides here can be recovered directly from the cell in a single, simplified step. The process also avoids the toxic solvents typically required, making it cleaner and more cost-effective.

A real target, real results

To put the technology through its paces, the team used it to go after CREB1, a transcription factor that is overactive in a broad range of cancers, including colorectal cancer. The peptides they identified didn’t just bind to the target in theory — they were shown to enter human cancer cells grown in the lab, shut down CREB1-controlled pathways, and selectively kill cancer cells.

That last word, selectively, is crucial. One of the biggest challenges in cancer treatment is sparing healthy cells from the damage. Peptides that can distinguish between normal and cancerous behavior represent a meaningful step forward.

What comes next

The research, published in Cell Chemical Biology, is still in its early stages. The next hurdle is demonstrating these results hold up in more complex tissue models and animal studies. But the platform itself is the real headline: a system that lets biology and chemistry work in concert to rapidly discover a new class of drugs for cancers that have long resisted treatment.

If it translates, it could open the door to tackling not just CREB1 but a whole family of transcription factors that scientists have been eyeing (and struggling to reach) for years.

This topic is featured in Great News podcast episode 39.

Source:

News Medical Net