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Oral peptide availability at last?
April 2018
by Kelsey Kaustinen  |  Email the author


MUNICH—Oral availability is something of an ideal in the pharmaceutical industry. It’s arguably the easiest form of drug administration, and certainly more likely to encourage patient compliance than subcutaneous injections. In the case of peptides, however, oral availability has been a pipe dream, something that is especially discouraging given the vast potential of peptides in pharmaceuticals. Roughly 500 peptide-based medications are in clinical trials at the moment, and that corner of the market is valued in the billions.
There might be light at the end of the tunnel now, though, thanks to news out of the Technical University of Munich (TUM) that details how to design peptides for liquid or tablet formulations.
“Peptides are wonderfully well-suited as medication,” said Horst Kessler, the Carl von Linde Professor at the Institute for Advanced Study at the 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.”
Kessler tells DDNews that he and his team have been studying peptides since about 1980. Some of their previous work included the study of cyclosporine, thanks to which, he says, “We knew that peptides containing high lypophilic amino acids like leucine or N-methylated peptides might be orally available, and from knowledge of some other natural products you can derive these peptides.” Cyclosporine is an 11 amino acid-peptide that can help suppress organ rejection following transplantation.
One of the biggest challenges of formulating peptides is the ubiquity Kessler speaks of—because proteins and amino acids (the latter of which comprise peptides) are a pivotal feature in the human body and diet, the digestive tract is home to dozens of digestive enzymes that destroy peptide bonds. Any peptides that could escape the stomach in one piece would be unable to be absorbed through the intestinal walls, rendering them impotent.
The team began with a ring-shaped model peptide consisting of six molecules of alanine, the simplest amino acid. They tested the peptide to see if and how replacing hydrogen atoms in the peptide bonds with methyl groups might impact oral availability, and generated more than 50 variations. Of those, only a few proved capable of being absorbed rapidly.
Kessler explains that “The cyclic hexapeptides are relatively rigid. We investigated first peptides containing only alanine, synthesizing a library of N-methylated derivatives. All together there are 63 different N-methylated alanine peptides of the type cyclo(D-Ala-Ala6) possible,” given the amino acids they used. "We synthesized almost 54 of these compounds, and then realized that the availability is extremely different. We have a few compounds of the alanine scaffold which are 100-percent orally available, and others are completely not.”
"The crucial point is then to introduce functional groups by substitution of alanine residues by amino acids, which are important for the biological function," he adds. "As these residues--in our case, Arg-Gly-Asp = RGD--have charges, we had to mask them for the oral uptake by residues which are, after the transport, easily cleaved in the blood serum, converting it in functional drugs."
Integrin receptors, which control multiple functions on the cell surface, were selected as a target for the peptides. Integrins function within the body by relaying information about a cell’s environment to the interior of the cell, and their malfunction can trigger a variety of diseases. There are 24 human integrins, and of those, eight subtypes recognize the sequence of arginine, glycine and aspartic acid. The sequence locks into the integrin receptor, and molecules and proteins with that sequence incite a reaction in the cell. The structure of that amino acid sequence affects which integrin receptor it slots into, and work is underway to identify molecules with the right sequences and the right spatial structure to enable them to trigger the same reactions in cells.
A sequence of arginine, glycine and aspartic acid is pivotal to docking at the integrin receptors and, as such, Kessler’s colleagues added the sequence at several different points on the model peptide. What they found was that the negatively charged side chain of aspartic acid and the positively charged arginine were knock-out criteria for the transport system, though both groups of amino acids could be masked with protecting groups. Though this eliminates the peptide’s ability to bind to its target molecule, certain protective groups will split off due to enzymes in the blood, thereby restoring pharmaceutical effect by the time the peptide reaches its target.
This recent work was partly covered in a paper published in Angewandte Chemie titled “Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3.”

“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,” Kessler noted. “In the future, this will greatly simplify the creation of peptide medication that can be easily given in fluid or tablet form.”
The compounds involved in this work were designed, synthesized and tested for biological activity at TUM in Garching, and were structurally characterized at the CSIR National Chemical Laboratory in Pune (India) and at the Università di Napoli Federico II in Italy. Cell systems at the Hebrew University in Jerusalem (Israel) were used to test permeability, while the biological effect in mice was examined at the Queen Mary University of London.
Code: E041802



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