Peptides do important work, and could be a largely untapped type of drug. The problem is they can’t be taken orally, because stomach acids destroy them before they can get into the bloodstream. Now, researchers at EPFL have developed a new method of testing and creating peptides that can survive this degradation and go on to do the therapeutic job they need to.
Peptides are basically small fragments of proteins. They’re made up of short chains of amino acids, usually between two and 50 amino acids long. Anything longer than that and it’s a protein. Like proteins, peptides perform a huge array of functions in the body, so they have great pharmaceutical potential. Insulin, for example, is a peptide hormone, and others are being explored for everything from treating cancer to fighting superbugs to patching up cavities in teeth.
But one limiting factor is that peptides dissolve very quickly in the gastrointestinal tract. After all, stomach acid is specifically honed to break down the bonds in proteins and peptides. That means they don’t work as pills or other oral medications, and must be injected or administered in other ways.
So the EPFL researchers set out to find a way to make peptides that can withstand this harsh environment. They built on their own previous work in what are known as double-bridged peptides, which are stronger but still not quite stable enough for practical use.
For the new study, the team developed a way to test which double-bridged peptides would not only survive the stomach but also have useful effects. Starting with billions of random peptide sequences, the team combined them with two chemical bridges to form the stronger double-bridged peptides.
These are then exposed to enzymes from the digestive tracts of cows, to sort out which ones can survive and which ones don’t. And finally, the types of peptides that do survive are then tested for whether they’ll have some beneficial effect. This is done by dipping certain proteins into the pool of peptides – if any peptides stick to the proteins, that means they’ll target that protein in the body.
Using this method, the researchers managed to identify a new peptide that’s both stable and therapeutic. It inhibits thrombin, an enzyme that’s involved in blood clotting and so is targeted to treat thrombosis. In animal tests, the researchers gave the new peptide to mice in pill form, and showed that it survived in their stomachs and intestines.
While it only reached the bloodstream in small amounts, the team noted that the peptide remained intact throughout their gastrointestinal tracts. That suggests that these oral peptides might be best suited to targeting problems in that part of the body.
“We are focusing on chronic inflammatory diseases of the gastrointestinal tract like Crohn's disease and ulcerative colitis as well as bacterial infections,” says Christian Heinis, lead researcher on the study. “We have already succeeded in generating enzyme-resistant peptides against the interleukin-23 receptor, an important target of these diseases, which affect millions of patients worldwide without any oral drug available.”
The research was published in the journal Nature Biomedical Engineering.
Source: EPFL
