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Peptides are short chain amino acids that exist in our bodies, plants, or bacteria to control multiple functions. Some peptides are used as drugs, such as insulin, which controls sugar metabolism; Cyclosporin, which can inhibit organ rejection after transplantation. More than 40 peptides have been approved as drugs, generating billions of dollars in revenue. Currently, hundreds of peptide based drugs are undergoing clinical trials.
Peptides are Intermediates Between Amino acids and Proteins
We know that proteins have various important functions in life activities, and the basic component of proteins is amino acids. Peptides are also composed of amino acids, but their size is not very large, and the key three-dimensional structure has not yet been fully formed. Therefore, to put it simply, peptides can be regarded as intermediates in the process of amino acid synthesis of proteins.
Peptides are long chains composed of amino acids, which are crucial elements for all life on Earth, “explained Professor Matthew Powner, the lead researcher of this study at University College London.” They can further form proteins and are responsible for biological processes.
Most Peptides are Difficult to Take Orally
But almost all of these drug peptides cannot be taken orally. Due to the fact that peptide is an important component of food, there are countless enzymes in the stomach and intestines that can degrade it, which means that most peptide based drugs cannot pass through the gastrointestinal tract.
Researchers hope to produce more stable peptides, where the ends of cyclic peptides are connected together through chemical bridges, making them more stable than linear peptides because their main chains are less flexible and therefore more difficult to attack by enzymes.
At present, the Omizzur biotech lab is conducting research and modification on the modification of peptides.
Development of Double Bridging Peptides
In 2020, the Christian Heinis research group of EPFL developed a new form of peptide called double bridging peptide, in which the peptide was cyclized by two chemical bridges that provide higher stability. Despite its success, most of these peptides are still unstable under the action of a large amount of proteases in the intestine.
Now, Heinis’ team has developed a new method to identify peptides from billions of double bridging peptides that can bind to disease targets and remain active in gastrointestinal enzymes. This method is published in the journal Nature Biomedical Engineering and involves three steps.
Firstly, 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. Secondly, this peptide library is exposed to enzymes in the bovine gut to eliminate all unstable peptides. In the third and final step, scientists immerse the target protein in the surviving peptide pool to identify those proteins that bind to the target disease. Heinis said, “It’s a bit like looking for a needle in a haystack, and this method makes everything simple
Targeted Peptides that can Resist Gastrointestinal Breakdown
Through this method, researchers have successfully developed a targeted peptide that can resist gastrointestinal breakdown for the first time. For example, they injected mice with a lead peptide in the form of tablets that inhibits thrombin formation, an important anti thrombotic target.
Peptides remain intact in the stomach and intestines, even though the amount they reach the bloodstream is small, most peptides remain intact throughout the entire gastrointestinal tract. This is a crucial step in designing oral peptide drugs.
Heinis’ team is currently applying this new method to develop oral peptides that directly act on gastrointestinal targets, which means they do not 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 targeting the interleukin-23 receptor, which is an important target for these diseases, affecting millions of patients worldwide without any oral medication.
More Peptide Synthesis Forms
Previously, many scientists were studying how amino acids spontaneously form peptides. But the conditions required for the reaction are extremely harsh and difficult to achieve. In this study, the team focused on the precursor molecule of amino acids – aminonitriles. They found that these molecules are inherently reactive and can directly form peptides without the need to first convert into amino acids. That is to say, researchers have found a way to synthesize peptides without the need for amino acids.
In addition to providing clues to the origin of life, this study also has contemporary practical application value. Researchers have pointed out that many biologically active molecules or synthetic materials require similar chemical reactions. Under normal synthesis conditions, we need to prepare many expensive materials in advance, resulting in waste. And these new reactions are expected to better serve synthetic biology and bring practical application value.
In the future, scientists plan to further explore more similar reactions, attempting to reduce peptide chains that can be naturally synthesized and elucidate their functions. Perhaps the mystery of the origin of life 4 billion years ago already exists in their laboratory!
References:
- De novo development of proteolytically resistant thermoplastic peptides for oral administration, Nature Biomedical Engineering (2020)
- Pierre Canavelli et al. (2019), Peptide ligation by chemoselective amino acid coupling in water, Nature, https://doi.org/10.1038/s41586-019-1371-4
