May 15, 2020 / BIOON / -- peptide is a short chain amino acid, which exists in our body, plants or bacteria to control multiple functions. Some peptides are used as drugs, such as insulin, which controls sugar metabolism; cyclosporine, which inhibits organ rejection after transplantation. More than 40 peptides have been approved as drugs, generating billions of dollars in revenue. Hundreds of peptide based drugs are currently in clinical trials.

But almost none of these peptides can be taken orally. Because peptide is an important part of food, there are countless enzymes in the stomach and intestines that can degrade them, which means that most peptide based drugs cannot pass through the gastrointestinal tract.

The researchers hope to produce more stable peptides, the ends of which are linked by chemical bridges, making them more stable than linear peptides, because their main chains are less flexible and therefore more difficult to attack by enzymes. In 2018, the Christian heinis team of EPFL developed a new form of peptide called Double Bridge peptide, in which the peptide is cyclized by two chemical bridges that provide higher stability. Despite its success, most of these peptides are not stable enough to act as a large number of proteases in the gut

Now, heinis's team has developed a new way to identify peptides that bind to disease targets and remain active in gastrointestinal enzymes from billions of double bridge peptides. This method is published in the Journal of nature biomedical engineering and involves three steps.

First, the random peptide sequences encoded by billions of genes are cyclized by two chemical bridges, which impose conformational constraints on the peptide skeleton, making them more difficult to be attacked by enzymes. Second, the peptide library is exposed to enzymes in the gut of cattle to eliminate all those unstable peptides. In the third and final step, the scientists dip the target protein into the surviving peptide pool to find out the proteins that bind to the target disease. "It's a bit like looking for a needle in a haystack, and this approach makes it easy," heinis said. "

In this way, researchers have successfully developed targeted peptides that can resist gastrointestinal decomposition for the first time. For example, they injected mice in the form of tablets with a leading peptide that inhibits thrombin formation, an important antithrombotic target. Peptides remain intact in the stomach and intestines, even though they reach a small amount of blood flow, most of them remain intact throughout the gastrointestinal tract. This is a key step in the design of oral peptide drugs.

Heinis's team is now using this new approach to develop oral peptides that act directly on gastrointestinal targets, which means they don't need to enter the bloodstream. "We focus on chronic inflammatory diseases of the gastrointestinal tract, such as Crohn's disease, ulcerative colitis, and bacterial infections. We have successfully produced anti enzyme peptides for IL-23 receptor, which is an important target of these diseases, affecting millions of patients all over the world without any oral drugs. (Biovalley )

reference material:

Peptides that can be taken as a pill

De novo development of proteolytically resistant therapeutic peptides for oral administration, Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-020-0556-360