A ground-breaking study at the Ecole Polytechnique Fédérale de Lausanne (EPFL) has developed orally available cyclic peptides, opening new possibilities for the development of drugs to treat various diseases, especially cancer. For decades, a large number of proteins critical for treating various diseases have remained difficult to treat with oral drugs. Traditional small molecule drugs often have difficulty binding to proteins with flat surfaces or require specificity for specific protein homologues. Typically, large biologics capable of targeting these proteins require injection, which limits patient convenience and accessibility.
In a new study published in the journal Nature Chemical Biology, scientists from the laboratory of Professor Christian Heinis at the Ecole Polytechnique Federale de Lausanne (EPFL) achieved an important milestone in the field of drug development. Their research opens the door to a new class of oral drugs and solves a long-standing problem for the pharmaceutical industry.
"There are many diseases where targets have been identified, but drugs that bind to them and hit the targets have not been developed," Hynes said. "Most of these are cancer types, and many of the targets in these cancers are protein-protein interactions that are important for tumor growth but cannot be inhibited."
The study focused on cyclic peptides, multifunctional molecules known for their high affinity and specificity in binding to challenging disease targets. Meanwhile, developing cyclic peptides into 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 because these molecules can bind to difficult targets for which generating drugs using established methods is challenging," Haynie said. "But cyclic peptides generally cannot be taken orally as tablets, which greatly limits their applications."
Cyclization breakthrough
The research team targeted thrombin, which is an important disease target because of its central role in the blood clotting process; regulating thrombin is key to preventing and treating thrombotic diseases such as stroke and heart attack.
To generate cyclic peptides that are stable enough to target thrombin, the scientists developed a two-step combinatorial synthesis strategy to synthesize a large library of cyclic peptides with thioether linkages that improve the metabolic stability of the cyclic peptides when administered orally.
"We have now successfully generated cyclic peptides that bind to our disease target of choice and that can also be orally administered," said Hynes. "To do this, we developed a new method to chemically synthesize thousands of small cyclic peptides with random sequences at the nanoscale and detect them in a high-throughput process."
Two steps and one pot
The new method's process involves two steps that take place in the same reaction vessel, a feature chemists call "one-pot."
The first step is to synthesize a linear peptide and then undergo a chemical process to form a cyclic structure, which is called "cyclization" in technical terms. This requires the use of "amphielectrophilic linkers" - compounds used to link two molecular groups together - to form stable thioether bonds.
In the second stage, the cyclized peptide undergoes acylation, a process in which a carboxylic acid is attached to the peptide, further enriching the peptide's molecular structure.
This technology eliminates intermediate purification steps and enables high-throughput screening directly on the synthesis plate, combining the synthesis and screening of thousands of peptides to identify candidate peptides with high affinity for a specific disease target - in this case, thrombin.
Using this approach, PhD student Manuel Merz, who led the project, generated a comprehensive library of 8,448 cyclic peptides with an average molecular mass of about 650 daltons (Da), just above the recommended maximum of 500 daltons for oral small molecule drugs.
These cyclic peptides also show high affinity for thrombin.
When tested on rats, the oral bioavailability of the peptide was as high as 18%, meaning that when the cyclic peptide drug was taken orally, 18% of the drug successfully entered the bloodstream and produced a therapeutic effect. Considering that the bioavailability of oral cyclic peptide drugs is usually less than 2%, increasing the bioavailability to 18% is a major advance for biologic drugs, including peptide drugs.
set goals
By making the cyclic peptide orally available, the team has opened up the possibility of treating a range of diseases that are difficult to treat with traditional oral drugs. The versatility of this approach means it can be tuned to target a variety of proteins, potentially leading to breakthroughs in areas of currently unmet medical need.
"Applying this approach to more challenging disease targets, such as protein-protein interactions, may require the synthesis and study of larger libraries. With more steps in the automated approach, libraries with more than 1 million molecules appear to be within reach," Manuel-Merz said.
In the next steps of the project, the researchers will target several intracellular protein-protein interactions for which it is difficult to develop inhibitors based on classical small molecules. They believe that oral cyclic peptides can be developed for at least some of these targets.
Compiled source: ScitechDaily