Oral Peptides: Revolutionizing Pharmaceutical Progress

For many years, numerous essential proteins crucial for treating diverse illnesses have proven challenging to administer through oral drug therapy. Conventional small molecules often face difficulties in binding to proteins with flat surfaces or necessitate specificity for specific protein homologs. Larger biologics, which can target these proteins, usually require injection, restricting patient convenience and accessibility.

In a recent publication in Nature Chemical Biology, researchers from Professor Christian Heinis’ laboratory at EPFL have made a significant breakthrough in the field of drug development. Their study marks a pivotal advancement, introducing a new category of drugs that can be taken orally—a solution to a persistent challenge in the pharmaceutical industry.

According to Heinis, “There are numerous diseases where the targets have been identified, but the development of drugs capable of binding to and reaching them has proven elusive. Many of these diseases, particularly various types of cancer, involve protein-protein interactions crucial for tumor growth but challenging to inhibit.”

Cyclic Peptides’ Potent Binding Properties Meet the Challenge of Oral Drug Development

The research centered on cyclic peptides, versatile molecules renowned for their high affinity and specificity in binding to complex disease targets. Despite these qualities, the development of cyclic peptides as oral drugs has been hindered by rapid digestion or poor absorption in the gastrointestinal tract.

Heinis explains, “Cyclic peptides are highly promising for drug development, as they can effectively bind to challenging targets that have been difficult to address using conventional methods. However, their limited applicability arises from the usual inability to administer cyclic peptides orally in pill form.”

In a recent article published in Nature Chemical Biology, scientists from Professor Christian Heinis’ laboratory at EPFL have achieved a significant breakthrough in the realm of drug development. Their study represents a crucial advancement, introducing a novel class of orally administered drugs as a solution to a persistent challenge in the pharmaceutical industry.

Heinis Highlights the Struggle to Develop Drugs Targeting Elusive Disease Targets

Heinis states, “There are numerous diseases where the identification of targets has occurred, but the development of drugs capable of effectively binding to and reaching these targets has remained elusive. Many of these diseases, particularly various types of cancer, involve protein-protein interactions essential for tumor growth but challenging to inhibit.”

The focus of the study was on cyclic peptides, versatile molecules well-known for their high affinity and specificity in binding to intricate disease targets. Despite these advantageous characteristics, the progress of cyclic peptides as oral drugs has been impeded by their rapid digestion or poor absorption in the gastrointestinal tract.

Heinis elaborates, “Cyclic peptides hold great promise in drug development, given their ability to efficiently bind to challenging targets that conventional methods have struggled to address. However, their practical application has been limited due to the common challenge of administering cyclic peptides orally in pill form.”

Two-step, Single-container Synthesis

The novel processing technique comprises two steps within the same reactive container, a characteristic referred to by chemists as a “one-pot” method.

In the initial step, linear peptides are synthesized, and subsequently, a chemical process cyclizes them, creating a ring-like structure. This cyclization is achieved using “bis-electrophilic linkers,” chemical compounds facilitating the formation of stable thioether bonds.

In the second phase, the cyclized peptides undergo acylation, a process that attaches carboxylic acids, enhancing their molecular diversity.

This approach eliminates the need for intermediary purification steps, facilitating high-throughput screening directly in the synthesis plates. Thousands of peptides can be synthesized and screened to identify candidates with high affinity for specific disease targets, such as thrombin in this case.

Generating a Vast Library of Cyclic Peptides Pushing Oral Small Molecule Limits

The method, led by Ph.D. student Manuel Merz, generated a comprehensive library of 8,448 cyclic peptides with an average molecular mass slightly above the recommended maximum limit for orally-available small molecules, at about 650 Daltons (Da).

These cyclic peptides exhibited high affinity for thrombin. In rat tests, the peptides demonstrated oral bioavailability up to 18%, a substantial advancement in comparison to the typical bioavailability below 2% for orally-administered cyclic peptides. This increased bioavailability is particularly significant for drugs in the biologics category, including peptides.

Targeting oral availability for cyclic peptides opens up possibilities for addressing challenging diseases that conventional oral drugs struggle to treat. The method’s adaptability allows it to be customized for various proteins, potentially leading to breakthroughs in areas where medical needs remain unmet.

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

In the next phase, the researchers plan to target intracellular protein-protein interaction targets that have been difficult to inhibit using classical small molecules, expressing confidence in the development of orally applicable cyclic peptides for at least some of them.

Read the original article on: Phys org

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