A harmless gut bacterium will be reprogrammed to churn out circular protein fragments called cyclic peptides, replacing toxic chemical manufacturing with a living factory. Cyclic peptides are an emerging class of drugs that can slip inside cells and latch onto disease-causing proteins, but 85% of human proteins are currently considered "undruggable" by conventional small-molecule drugs or antibodies. Existing cyclic peptide production relies on unsustainable, toxic chemicals, limiting their development. The researcher will engineer bacteria to both produce cyclic peptides and rapidly screen millions of variants to find the one that best binds a target—a process that currently requires separate, resource-intensive steps. If successful, this bio-based platform could offer a clean, high-yielding route to cyclic peptide drugs, particularly for cancer targets that have resisted treatment. The immediate impact is on pharmaceutical manufacturing and drug discovery pipelines, shifting away from hazardous chemistry toward a sustainable biological process. While the work is still at the fundamental stage, it directly addresses a bottleneck in turning an underexploited drug class into real therapies.
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Protein-protein interactions (PPI) govern essential biochemical processes in all living organisms, and dysregulation of PPIs are linked to numerous diseases including cancer, autoimmune and neurodegenerative disorders. Consequently, modulating the interactions between proteins is essential for unlocking new therapeutics. However, 85% of all proteins are currently considered “undruggable” by the two major classes of therapeutics: Small molecule drugs are cheap to produce, can enter cells, but have limited ability to influence PPIs due to their small size. On the other hand, antibodies show excellent engagement to target proteins, but its large molecular size limits entry to cells preventing access to many therapeutically relevant targets. Cyclic peptides are strings of amino acids arranged in a circular pattern. Relative to most drugs, they have an intermediate molecular size (1-3 kDa) which allows entry into cells while showing strong target engagement. Cyclisation also confers structure and resistance to biological breakdown, and therefore cyclic peptides are an emerging class of therapeutics offering access to the undruggable 85%, attracting significant interest from researchers in academia and the pharmaceutical industry. However, cyclic peptide production is challenging. Existing methods employ toxic and unsustainable chemicals which limits development of cyclic peptide drugs. Machinery to produce cyclic peptides exist in nature, in tropical flowering plants such as the Butterfly Pea, which produces cyclic peptides as a defence mechanism against pests. During my fellowship, I will reprogram a harmless gut bacterium to mimic nature and produce cyclic peptides inside live cells, and therefore create a bio-based technology to generate a step change towards a high yielding, clean and green cyclic peptide production methodology that shifts away from toxic and unsustainable chemicals. Additionally, the bacteria will be programmed to rapidly sift through millions of cyclic peptide sequences to select the one that is best at engaging the drug target. I will use the engineered bacteria to identify cyclic peptides that target cancer causing proteins which are historically considered “undruggable” and deliver several leads with the long-term goal of developing into new cancer therapeutics.
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