Reviewed by James Ives, M.Psych. (Editor)

Milestone for therapeutic development of peptides against gastrointestinal disorders

The fascinating family of trefoil factor peptides brings hope to both research and industry to improve the treatment of chronic disorders such as Crohn’s disease.

For the first time, a team led by ERC awardee Markus Muttenthaler from the Faculty of Chemistry of the University of Vienna succeeded in the synthesis and folding of the peptide TFF1, a key player in mucosal protection and repair.

Chemical synthesis of these gastrointestinal peptides is an important step towards a better understanding of their mode of action and therapeutic potential. The study was published in “Chemical Communications”.

Markus Muttenthaler, ERC Awardee, Faculty of Chemistry, University of Vienna

The three known human trefoil factor family peptides TFF1, TFF2, and TFF3 are mainly produced by the gastrointestinal mucosa. Named after their trefoil-like folded structure, the molecules provide clinically intriguing properties.

Studies demonstrated that these peptides are locally produced to combat inflammation and injuries of the gastrointestinal tract by accelerating wound healing. Therefore, they have considerable therapeutic potential for gastrointestinal and other mucosal disorders such as dry eye disease and asthma as the researcher’s state in an additional review article published in “ACS Pharmacology & Translational Science”.

Local effects
“To date, there are two oral peptide therapeutics against diseases such as irritable bowel syndrome on the market,” says the medicinal chemist Muttenthaler.

“Due to the relatively large size of the molecules, they are not being absorbed through the gastrointestinal wall into the bloodstream, and therefore can only act locally in the gastrointestinal tract without major side effects.”

The trefoil factor family is “an essential starting point for new therapeutic strategies to treat chronic diseases that remain incurable”, explains Muttenthaler, who leads research groups at the Department of Biological Chemistry at the University of Vienna and at the University of Queensland in Brisbane.

The studies are being conducted in the context of Muttenthaler’s ERC Starting Grant project, which aims at disclosing the mechanisms of wound healing in the gastrointestinal tract. “Based on the chemical synthesis of the TFF peptides, we can now find answers to fundamental questions that we were not able to tackle before.”

TFF1 acts as a homodimer
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In their study, the researchers present the chemical synthesis of TFF1 and its homodimer, a molecule that comprises two TFF1 subunits. Only in its homodimeric form was TFF1 able to interact with mucins, main structural constituents of the gastrointestinal tract, which accelerates the closure of the mucosal barrier and its healing process.

With a length of 60 amino acids, conventional approaches were not applicable to the synthesis of TFF1. The scientists developed a new method to synthesize the peptide in two fragments and assemble them subsequently. The second challenge that the scientists had to overcome was to fold TFF1 correctly by selecting from a multitude of possibilities.

Correct folding was then confirmed through structural analysis and the TFF1 homodimer was shown to interact with the gastric mucosa. Muttenthaler and his team now work on the chemical synthesis of the other two members of the trefoil factor family, TFF3 and the more challenging TFF2, which is longer and more complex with its 106 amino acids and 7 disulfide bonds.

New possibilities for molecular design
The chemical synthesis of TFF1 is a milestone for the field since it provides more options to modify this peptide class. To date, recombinant expression was the only way to produce these molecules. “Therefore, their design was limited to the 20 natural amino acids.

Chemical synthesis now enables us to design advanced TFF1 probes to study their mechanisms of action or to optimize TFF1 towards its therapeutic applications”, Muttenthaler explains.

Molecular probes are essential for a better understanding of TFF1 and its mode of action. Certain attachments such as fluorescent molecules or other reporter tags can help to study TFF1 interactions with its target proteins or receptors.

Other modifications could be used to further improve the stability of the peptides and their drug-like properties for a more efficient therapeutic application.