February 21, 2024

Oral Peptides A Revolutionary Breakthrough in Drug Development

In a remarkable achievement that marks a new era in drug development, researchers from EPFL have made a groundbreaking advancement in the field of pharmaceuticals. Their study, published in Nature Chemical Biology, introduces a novel approach to creating orally available drugs using cyclic peptides. This development has the potential to address a long-standing challenge in the industry, as many proteins vital for treating various diseases have remained elusive to oral drug therapy.

Traditional small molecules have struggled to bind to proteins with flat surfaces or require specificity for particular protein homologs. On the other hand, larger biologics that can target these proteins often necessitate injection, limiting patient convenience and accessibility. The focus of this study was to overcome these limitations and pave the way for a new class of orally available drugs.

Cyclic peptides are known for their high affinity and specificity in binding challenging disease targets. However, developing them as oral drugs has proven difficult due to difficulties with digestion and poor absorption in the gastrointestinal tract. To overcome these obstacles, the research team aimed to synthesize cyclic peptides that could target the enzyme thrombin, which plays a critical role in blood coagulation.

To achieve this, the scientists developed a two-step combinatorial synthesis strategy to create a large library of cyclic peptides with thioether bonds. These bonds enhance the metabolic stability of the peptides when taken orally. The research team successfully generated cyclic peptides that bind to thrombin and can be administered orally, which is a significant achievement.

The synthesis of the cyclic peptides involved a two-step process conducted in the same reactive container, also known as “one pot” by chemists. In the first step, linear peptides were synthesized, followed by a process of cyclization using bis-electrophilic linkers to form stable thioether bonds. In the second phase, acylation was performed to further diversify the molecular structure of the cyclized peptides.

The advantage of this method is that it eliminates the need for intermediate purification steps, enabling high-throughput screening directly in the synthesis plates. This efficient process allowed for the synthesis and screening of thousands of peptides to identify candidates with high affinity for thrombin.

Using this approach, the researchers generated a comprehensive library of 8,448 cyclic peptides with an average molecular mass slightly above the recommended limit of 500 Daltons (Da) for orally-available small molecules. These cyclic peptides demonstrated a high affinity for thrombin, making them promising candidates for oral drug therapy.

In animal testing on rats, the orally administered cyclic peptides exhibited a bioavailability of up to 18%. This means that 18% of the drug successfully enters the bloodstream and has a therapeutic effect. Considering that orally-administered cyclic peptides typically have a bioavailability below 2%, this remarkable improvement could revolutionize the field of biologics that include peptides.

The successful oral delivery of cyclic peptides opens up possibilities for treating a wide range of diseases that have proven challenging to address with conventional oral drugs. The method’s versatility allows for adaptation to target various proteins, potentially leading to breakthroughs in areas where medical needs remain unmet.

The researchers envision the application of this method to more challenging disease targets, such as protein-protein interactions. To accomplish this, larger libraries will need to be synthesized and studied. Automation of further steps in the process could facilitate the creation of libraries with over one million molecules.

In the next phase of the project, the researchers plan to target several intracellular protein-protein interaction targets that have been difficult to inhibit using conventional small molecules. They are optimistic that they can develop orally applicable cyclic peptides for at least some of these targets, further expanding the range of treatable diseases.

In conclusion, the development of orally available cyclic peptides represents a monumental leap forward in drug development. This breakthrough has the potential to revolutionize the pharmaceutical industry by addressing the limitations of traditional oral drugs and opening up new possibilities for treatment. With further research and refinement, this groundbreaking approach could transform the lives of millions of patients worldwide.

1. Source: Coherent Market Insights, Public sources, Desk research
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