Method Developed for Generating Orally Available Cyclic Peptides

For decades, the pharmaceutical industry has struggled to develop oral peptides that can bind challenging disease targets with high affinity and specificity and thus have tremendous potential to treat a wide range of diseases. Traditional small molecules have faced limitations in binding to proteins with flat surfaces or require specificity for particular protein homologs, while larger biologics that can target these proteins required injections, reducing patient convenience. In a new study published in Nature Chemical Biology, researchers at EPFL have developed a method to generate orally available drugs that address this longstanding pharmaceutical hurdle.

The focus of the study was on cyclic peptides, versatile molecules known for their high affinity and specificity in binding challenging disease targets. While these peptides hold promise, their rapid digestion and poor absorption by the gastrointestinal tract hindered their development as oral drugs. The research team targeted the enzyme thrombin, crucial in blood coagulation, using a two-step combinatorial synthesis strategy to create cyclic peptides with enhanced metabolic stability.

The innovative technique, referred to as "one pot," combines two steps in the same reactive container. The first step involves synthesizing linear peptides, followed by the formation of a ring-like structure through cyclization using bis-electrophilic linkers. The second phase, acylation, further diversifies the molecular structure without requiring intermediate purification steps.

The researchers successfully generated a library of 8,448 cyclic peptides with an average molecular mass slightly above the recommended limit for orally available small molecules. Testing on rats demonstrated oral bioavailability up to 18%, a substantial advancement considering the typical bioavailability for orally administered cyclic peptides is below 2%.

This advance opens up possibilities for treating diseases challenging to address with conventional oral drugs. The method's adaptability suggests it could target a wide array of proteins, potentially leading to breakthroughs in areas with unmet medical needs. The researchers aim to apply the method to challenging disease targets, such as protein-protein interactions, with the goal of developing orally applicable cyclic peptides for a range of diseases.