Bacterial Technology Unlocks New Pathway for 'Undruggable' Cancers
Researchers at the University of Bath have developed a new technology that utilizes bacteria to construct, chemically stabilize, and test millions of potential drug molecules within living cells. This innovative method aims to accelerate the discovery of new treatments for challenging cancers.
The technology involves bacteria producing large libraries of peptide molecules. These peptides are then chemically stabilized, or 'stapled,' into specific shapes while being tested inside the cell. Only bacteria that generate effective and non-toxic peptides survive, enabling rapid identification of promising drug candidates. This integrated approach combines chemical modification and biological testing, streamlining the drug discovery process.
Targeting Critical Cancer Pathways
The team has applied this technology to identify peptide inhibitors of transcription factor CREB1, which exhibits overactivity in various cancers, including colorectal cancer. These identified peptides have been demonstrated to enter human cancer cells in laboratory settings, deactivate CREB1-controlled pathways, and selectively eliminate cancer cells.
Peptides, which are short chains of amino acids, are being investigated as potential drugs for 'undruggable' cancer drivers known as transcription factors. These proteins regulate gene activity and are frequently overactive in cancerous conditions.
In-Cell Stapling and Rapid Screening
The study, published in Cell Chemical Biology, details a bacterial system where each bacterium produces a distinct peptide. This peptide undergoes chemical modification within the living cell, which acts as a molecular staple to lock it into a defined shape. This in-cell stapling allows for the direct testing of millions of structurally stabilized peptides in a biological environment.
The modified peptides are screened using the Transcription Block Survival (TBS) assay, a technique where bacteria survive only if the peptide they produce successfully blocks the cancer-causing transcription factor. By combining chemical peptide stabilization with the TBS assay, researchers can simultaneously generate and screen tens of millions of stapled peptide variants for their ability to deactivate a transcription factor target. Effective stapled peptides become dominant in the bacterial population, while unstable, ineffective, or toxic peptides are eliminated.
A Greener, More Efficient Discovery Method
This approach is considered cleaner, greener, and more cost-effective than conventional peptide drug discovery methods. It bypasses the need for toxic solvents and multi-step chemical processes typically required for creating and stapling peptides in a laboratory setting.
Traditional methods involve multiple steps of making, purifying, modifying, and re-purifying peptides. In contrast, stapled peptides can be retrieved directly from the cell in a single, simplified step, enhancing scalability for potential large-scale production.
"This approach is considered cleaner, greener, and more cost-effective than conventional peptide drug discovery methods."
Expert Perspectives
Dr. Andrew Brennan, from the University of Bath, noted that the method allows for the chemical stabilization and testing of millions of different peptides inside the cell, with the most effective candidates naturally emerging.
"The method allows for the chemical stabilization and testing of millions of different peptides inside the cell, with the most effective candidates naturally emerging."
Professor Jody Mason highlighted the significance of finding peptides that are chemically stabilized, resistant to breakdown, and functional within live cells, which could address previously 'undruggable' cancer targets.
"Finding peptides that are chemically stabilized, resistant to breakdown, and functional within live cells could address previously 'undruggable' cancer targets."
What's Next
The next phase of research will involve testing these peptide inhibitors in more complex tissue models and animal studies.