A groundbreaking study at EPFL has led to the development of orally available cyclic peptides, offering new possibilities in drug development for various diseases, especially cancer.
For decades, a substantial number of proteins, vital for treating various diseases, have remained elusive to oral drug therapy. Traditional small molecules often struggle to bind to proteins with flat surfaces or require specificity for particular protein homologs. Typically, larger biologics that can target these proteins demand injection, limiting patient convenience and accessibility.
In a new study published in the journal Nature Chemical Biology, scientists from the laboratory of Professor Christian Heinis at EPFL have achieved a significant milestone in drug development. Their research opens the door to a new class of orally available drugs, addressing a long-standing challenge in the pharmaceutical industry.
“There are many diseases for which the targets were identified but drugs binding and reaching them could not be developed,” says Heinis. “Most of them are types of cancer, and many targets in these cancers are protein-protein interactions that are important for the tumor growth but cannot be inhibited.”
The study focused on cyclic peptides, which are versatile molecules known for their high affinity and specificity in binding challenging disease targets. At the same time, developing cyclic peptides as oral drugs has proven difficult because they are rapidly digested or poorly absorbed by the gastrointestinal tract.
“Cyclic peptides are of great interest for drug development as these molecules can bind to difficult targets for which it has been challenging to generate drugs using established methods,” says Heinis. “But the cyclic peptides cannot usually be administered orally – as a pill – which limits their application enormously.”
Cyclizing Breakthrough
The research team targeted the enzyme thrombin, which is a critical disease target because of its central role in blood coagulation; regulating thrombin is key to preventing and treating thrombotic disorders like strokes and heart attacks.
To generate cyclic peptides that can target thrombin and are sufficiently stable, the scientists developed a two-step combinatorial synthesis strategy to synthesize a vast library of cyclical peptides with thioether bonds, which enhance their metabolic stability when taken orally.
“We have now succeeded in generating cyclic peptides that bind to a disease target of our choice and can also be administered orally,” says Heinis. “To this end, we have developed a new method in which thousands of small cyclic peptides with random sequences are chemically synthesized on a DOI: 10.1038/s41589-023-01496-y