The field of medicine is evolving rapidly, and experts have carried out extensive efforts to implement alternative delivery strategies. For decades, scientists have struggled to develop oral drug therapy that can treat various diseases.
Challenges in Administering Oral Drugs
Experts sometimes identify the targets for certain diseases but fail to develop drugs that bind and reach them. Most of them are types of cancer where the targets are protein-protein interactions essential for tumor growth.
Many proteins with the potential to treat diseases have remained elusive to oral drug therapy for many years. Traditionally, small molecules struggle to bind to proteins with flat surfaces or require specificity for particular protein homologs. Meanwhile, larger biologics targeting such proteins need injection, thus limiting patient convenience and accessibility.
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New Era in Drug Development
Experts from Ecole Polytechnique Federale de Lausanne (EPFL) have achieved an important milestone in drug development. Their research, "De novo development of small cyclic peptides that are orally bioavailable," paves the way for a new class of orally available drugs that can address a long-standing challenge in the pharmaceutical industry.
Led by EPFL professor Christian Heinis, the research team focuses on cyclic peptides, a versatile type of molecule with high affinity and specificity in binding disease targets. Cyclic peptides are very interesting for drug development because they can bind to difficult targets.
However, cyclic peptides cannot usually be administered orally as a pill, limiting their enormous application. Developing these molecules as oral drugs has proven difficult because they are either digested rapidly or absorbed poorly by the gastrointestinal tract.
To address this challenge, the team targeted the enzyme thrombin, a critical disease target with a central role in blood coagulation. Regulating this enzyme can help prevent and treat thrombotic disorders like strokes and heart attacks.
The scientists developed a two-step combinatorial synthesis strategy to generate cyclic peptides that are sufficiently stable to target thrombin. This approach aims to synthesize a vast collection of cyclic peptides with other bonds, enhancing their metabolic stability when administered orally.
This strategy eliminates the need for intermediate purification steps, enabling high-throughput screening directly in the synthesis plates. It also combines the synthesis and screening of thousands of peptides to identify candidates with high affinity for thrombin. When the method was tested on rats, the peptides showed up to 18% oral bioavailability. This means that when the cyclic peptide drug is taken orally, 18% of it enters the bloodstream successfully.
By allowing the oral availability of cyclic peptides, the researchers have opened up possibilities for treating various diseases that have been challenging to address with conventional oral drugs. The method's versatility means that it can be adapted to target a wide array of proteins, possibly leading to breakthroughs in areas where medical needs are usually unmet. In the future, Heinis and his colleagues plan to target several intracellular protein-protein interaction targets for which it has been difficult to develop inhibitors based on small molecules.
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