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Oral peptides pave the way for new drug development

A new study led by EPFL Professor Christian Heinis heralds a new era in drug development, particularly for oral peptides. 

The research bridges a critical gap in pharmaceuticals, especially in treating diseases where protein targets have been elusive to oral drug therapy.

Drug development barriers

For years, the pharmaceutical industry has struggled with the challenge of developing oral drugs that effectively target specific proteins. 

Traditional small molecules often fall short in binding to proteins with flat surfaces or require specificity for certain protein homologs. Larger biologics, although capable of targeting these proteins, typically require injection, posing limitations in terms of patient convenience and accessibility.

Cyclic peptides

The EPFL team has made a significant breakthrough in creating a new class of orally available drugs. The research primarily revolves around cyclic peptides, molecules known for their strong affinity and specificity in binding to challenging disease targets.

“There are many diseases for which the targets were identified but drugs binding and reaching them could not be developed,” said 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.”

Challenges and solutions 

Developing cyclic peptides as oral drugs has historically been difficult due to their rapid digestion or poor absorption in 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,” explained Heinis. “But the cyclic peptides cannot usually be administered orally – as a pill – which limits their application enormously.”

Targeting thrombin

The research was focused on the enzyme thrombin, a key player in blood coagulation and a critical disease target for preventing thrombotic disorders. 

The team developed a novel two-step combinatorial synthesis strategy to create a vast library of cyclical peptides with enhanced 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,” said 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.”

Synthesis and screening 

The synthesis process involves two key steps in the same reactive container, simplifying the procedure. Initially, linear peptides are synthesized and then cyclized using bis-electrophilic linkers to form stable thioether bonds. Subsequently, these peptides undergo acylation, diversifying their molecular structure.

This technique, bypassing intermediate purification steps, allows for direct high-throughput screening in the synthesis plates. The combination of synthesis and screening paves the way for identifying candidates with high specificity for disease targets, like thrombin.

Promising results

Manuel Merz, a PhD student leading the project, successfully generated a library of 8,448 cyclic peptides with high affinity for thrombin. 

Notably, when tested on rats, these peptides exhibited an oral bioavailability of up to 18%, a remarkable improvement over the typical bioavailability of less than 2% for orally administered cyclic peptides.

Broader implications 

The breakthrough study sets the stage for treating a variety of diseases that have been challenging to address with conventional oral drugs. The versatility of this method promises applications across a broad spectrum of proteins, potentially leading to significant advancements in areas with unmet medical needs.

The team plans to expand their approach to more challenging disease targets, like protein-protein interactions. By automating further steps, they aim to synthesize and study even larger libraries of molecules.

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

The study is published in the journal Nature Chemical Biology.

Image Credit: Christian Heinis/EPFL

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