Oral Peptides: A New Era in Drug Development

In a new study scientists 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. 

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.

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 nanoscale and examined in a high-throughput process.”

By enabling the oral availability of cyclic peptides, the team has opened up possibilities for treating a range of diseases that have been challenging to address with conventional oral drugs. The method’s versatility means it can be adapted to target a wide array of proteins, potentially leading to breakthroughs in areas where medical needs are currently unmet.

“To apply the method to more challenging disease targets, such as protein-protein interactions, larger libraries will likely need to be synthesized and studied,” says Manuel Merz. “By automating further steps of the methods, libraries with more than one million molecules seem to be within reach.”

In the next step of this project, the researchers will target several intracellular protein-protein interaction targets for which it has been difficult to develop inhibitors based on classical small molecules. They are confident that orally applicable cyclic peptides can be developed for at least some of them.


Materials provided by Ecole Polytechnique Fédérale de Lausanne. Original written by Nik Papageorgiou. The original text of this story is licensed under Creative Commons CC BY-SA 4.0. Note: Content may be edited for style and length.

Manuel L. Merz, Sevan Habeshian, Bo Li, Jean-Alexandre G. L. David, Alexander L. Nielsen, Xinjian Ji, Khaled Il Khwildy, Maury M. Duany Benitez, Phoukham Phothirath, Christian Heinis. De novo development of small cyclic peptides that are orally bioavailable. Nature Chemical Biology, 2023; DOI: 10.1038/s41589-023-01496-y

Ecole Polytechnique Fédérale de Lausanne. “Oral peptides: A new era in drug development.” ScienceDaily. ScienceDaily, 9 January 2024. <www.sciencedaily.com/releases/2023/12/231228145735.htm>.

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