Researchers may have found a way to administer peptide therapies orally

Research from a team led by the Technical University of Munich (TUM) has uncovered a breakthrough in peptide chemistry that may enable the administration of peptide active agents orally.

“Peptides are wonderfully well-suited as medication,” explained Horst Kessler, Carl von Linde Professor at the Institute for Advanced Study at TUM. “The body already uses them as signaling molecules, and when they have done their job, they can be recycled by the body — no accumulation, no complicated detoxification.”

Despite their usefulness, however, oral administration of peptide based medications is a challenge due to difficulties surrounding their absorption into the blood stream through the stomach and intestinal walls.

Initially, the researchers at TUM approached these challenges by using a ring-shaped model peptide. With this first model, the team investigated the impact of replacing hydrogen atoms of the peptide bonds with methyl groups on oral availability.

From these experiments, the team developed 50 variations. Through a collaboration with partners in Israel, who performed cellular tests, the absorption rates were determined, which revealed that only specific peptide variants were absorbed rapidly.

“It appears that cyclic hexapeptides with a specific structure are able to use an existing transport system,” added Kessler.

Integrin receptors were chosen by the TUM team as the target for peptide therapy as they control a variety of functions on the cell surface. To dock at these receptors, however, a specific sequence of three amino acids (arginine, glycine and aspartic acid) is key. Working with this information, the researchers incorporated the key sequence at different positions on their cyclic peptide model.

A challenge in transportation turned up, however, both the negatively charged side chain of aspartic acid and the positively charged arginine turned out to be knock-out criteria. Masking of these charged groups was performed with protecting groups, which meant that the peptide initially lost its ability to bind to the target molecule. However, selection of the right protective groups meant that they could be removed by enzymes once the protected peptide entered the blood enabling the pharmaceutical effect to be restored.

In mice models that were fed the masked hexapeptide, the pharmacological effect was found to be the same as those in mice that were injected with the unmasked form, therefore demonstrating the biological effect of this new therapy.

“In the past, experts have designated the oral availability of peptide-based medications as the ‘holy grail of peptide chemistry’. Our work provides a strategy for solving the challenges of stability, absorption in the body and biological effectiveness,” revealed Kessler. “In the future, this will greatly simplify the creation of peptide medication that can be easily given in fluid or tablet form.”