Peptide therapeutics are experiencing a surge of interest, driven by significant advances, including the blockbuster success of weight loss drugs like semaglutide and tirzepatide. With more than 80 peptide drugs already on the market and hundreds more in clinical and preclinical development, the global market for peptide-based therapeutics is expected to grow to $68.83 billion by 2028.
Despite their promise, discovering and developing peptide drugs is far from straightforward. Peptides are often structurally flexible, easily degraded by enzymes in the body, and can struggle to enter cells, limiting their stability and effectiveness as drugs.
One promising strategy to overcome these challenges is peptide stapling, a technique that chemically locks peptides into a stable shape. But even with stapling, discovering peptides that are both potent and drug-like is a major bottleneck. Traditional discovery methods require peptides to be synthesized, modified, purified, and tested in multiple steps — an often slow and resource-intensive process.
Now, researchers at the University of Bath have developed a revolutionary approach that leverages bacteria to do the heavy lifting in drug discovery. Their new system, published in Cell Chemical Biology, uses bacteria to produce, chemically stabilize, and test millions of peptide molecules inside living cells, all in a single, streamlined process. The result is a faster, cleaner, and more scalable way to identify potential therapies for proteins that have long resisted conventional drug development.
Letting bacteria do the hard work
A key innovation behind the Bath platform is the use of stapled peptides, chemically constrained molecules that maintain a stable, biologically active shape. Many peptides naturally adopt specific structures when binding to their targets, but outside of the cell, they are flexible and prone to losing this shape. This instability limits their effectiveness as drugs.
Overall, stapling can transform a weak peptide into something much closer to a drug-like molecule
—Jody Mason, University of Bath
“Many biologically active peptides adopt an alpha-helical structure when they bind their targets, but in solution they often flop around and lose that structure,” Jody Mason, senior author of the study and biochemist at the University of Bath, explained to DDN. “By inserting a chemical crosslink, known as a staple, between two residues, we can stabilize the helix. That stabilization provides several benefits. It can provide improved binding to the target, increased resistance to degradation, and potentially improved ability to enter cells. Overall, stapling can transform a weak peptide into something much closer to a drug-like molecule.”
In the Bath system, these stapled peptides aren’t made in a test tube — they’re produced directly inside living bacterial cells. “Rather than synthesizing peptides and then chemically stapling them afterwards, we asked whether we could carry out the stapling reaction inside living cells during the screening process itself,” Mason said. “By doing so, the biology effectively selects both the peptide sequence and the optimal constraint geometry at the same time.”
Peptides are expressed in bacteria as part of genetically encoded libraries, with each cell producing a unique sequence. The researchers then add small bis-alkylating molecules into the bacterial culture. These molecules cross the bacterial membrane and react with pairs of cysteine residues engineered into the peptides, forming the staple and cyclizing the molecule inside the living cell.
Instead of creating peptides in the lab and modifying them in multiple steps, this new approach allows millions of candidate molecules to be generated simultaneously inside bacteria. This dramatically speeds up the discovery process and reduces the need for complex, multi-step synthesis and purification that traditionally slows peptide drug development. It also makes the method cleaner, greener, and highly scalable, with the potential to accelerate peptide therapeutics discovery far beyond what conventional lab methods can achieve.
Screening by survival
The magic of the Bath platform lies not just in producing and stapling peptides inside bacteria, but in how it identifies the most promising candidates. This is done using a system called the Transcription Block Survival (TBS) assay, which links peptide activity directly to bacterial survival.
In this setup, the bacteria are engineered so that a transcription factor — a protein the team wants to inhibit — blocks the expression of an essential gene. If the transcription factor is active, the cell cannot grow. But if a peptide successfully blocks the transcription factor, the block is lifted, and the cell survives.
“The TBS assay automatically filters out sequences that are unstable, non-specific, toxic, or poorly expressed,” Mason explained. “Only peptides that are stable, functional, and able to selectively engage the target inside the cell allow their host cells to grow.”
This approach is not only fast and efficient, but it also ensures that the peptides identified are more likely to be functional in human cells, since they must withstand a living cellular environment to succeed. It represents a dramatic shift from traditional peptide discovery, where each molecule must be painstakingly synthesized, modified, and tested in multiple steps.
Targeting CREB1
For their proof-of-concept, Mason’s team focused on CREB1 (cAMP responsive element binding protein 1), an oncogenic transcription factor implicated in multiple cancers. CREB1 regulates genes involved in cell proliferation, survival, and metastasis, making it a high-value but historically “undruggable” target.
“Transcription factors like CREB1 are often considered undruggable because their interaction surfaces are difficult for small molecules to target,” Mason noted. “What was exciting in this study was that the screening platform produced cyclic peptides with nanomolar binding affinity that could disrupt the CREB1–DNA interaction. When made cell-permeant, the lead peptide suppressed CRE-dependent transcription and reduced cancer cell viability.”
After identifying promising peptides in bacteria, the team synthesized the hits and tested them in biochemical and cellular assays. These tests confirmed that the peptides bind CREB1, disrupt protein–DNA interactions, enter human cancer cells, and selectively kill cancer cells in the lab.
A highly flexible platform approach
The University of Bath team’s approach represents a major shift in how peptide therapeutics can be discovered and optimized. By allowing the biology to “choose” the most functional peptides, the system can explore millions of candidates in a single experiment, vastly increasing the efficiency of discovery.
“This technology opens up completely new ways to go after cancer targets that have long been considered undruggable,” Mason says. “We’re not just finding peptides that bind a target — we’re finding peptides that are chemically stabilized, resistant to breakdown, and functional inside live cells.”
While the current study focused on CREB1, the core technology is highly adaptable. Any protein interaction that can be coupled to a genetic selection readout could, in principle, be targeted, opening possibilities across oncology, infectious disease, and other therapeutic areas.
As the team moves toward testing their peptides in more complex tissue models and animal studies, the Bath platform stands as a blueprint for next-generation peptide therapeutics. By combining scalability, flexibility, and in-cell validation, it could transform the discovery of drugs against the most elusive and medically important protein targets, giving researchers new tools to tackle diseases that have long defied conventional therapies.
