Advances in the development of orally available peptide drugs

Researchers hijack existing peptide absorption mechanism through intestinal walls to help develop novel oral cancer therapies.

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Feb 22, 2018
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A group led by Horst Kessler, Professor of Chemistry at the Technical University of Munich (Munich, Germany) have shown how a methylated peptide hexamer can be used hijack existing transport systems to allow its uptake through the intestinal cell wall. The team used this method to administer an integrin binding motif, which could be used for future cancer therapeutics.

Peptides are short chains of amino acids used by the body in cell signalling, making them ideal candidates for novel therapies. While a large number of peptide drugs are currently in use or undergoing clinical trials, their functionality is limited by their inability to be administered orally.

Oral administration is hampered by digestive enzymes, such as protease, which break down the peptide bonds between amino acids and ciliated intestinal cells, which prevent absorption into blood.

By taking a cyclic hexapeptide of alanine and methylating various hydrogen atoms to shield the bond, Kessler’s team was able to hijack an existing transport mechanism that allows intestinal uptake of the peptide. The researchers’ next step was to see if a more functional peptide could be made orally bioavailable.

Integrin receptors sit on the outside of cell membranes and can be activated by a simple peptide motif of arginine, glycine and aspartic acid. The group attempted to integrate this sequence into their hexapeptide model but found that the negatively charged group on arginine and positively charged aspartic acid prevented use of the existing transport system across the intestinal wall.

To tackle this problem, the team masked the charged moieties with protecting groups. These groups allowed the hexapeptide to cross the intestinal wall but prevented binding to the target. By carefully selecting protecting groups, the group ensured these could be cleaved by enzymes present in blood to reveal the active motif.

This structure was shown to have a biological effect by stimulating the growth of blood vessels in mice, a ground-breaking result, as Kessler commented: "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. In the future, this will greatly simplify the creation of peptide medication that can be easily given in fluid or tablet form."

In tumors, integrin receptors are activated to stimulate blood vessel growth, securing a blood supply to the tumor. By interfering with the integrin signalling pathway, there is hope that this research could lead to the development of novel, orally-available cancer therapeutics. Kessler’s group is now looking for new, similar signalling motifs, to integrate into the hexamer structure. 


Weinmüller M, Rechenmacher F, Kiran Marelli U, et al. Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3. Angew. Chem. Int. Ed. Engl. 56(51) 16405-16409 (2017);

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Benjamin Walden

Commissioning Editor, Future Science

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