Peptides for recovery as active ingredients are less in the limelight than proteins. There was good reason for that. However, there are increasing signs that these ‘small proteins‘ are now increasingly pushing themselves into the spotlight of biologicals. In fact, their pharmacological rise has already begun.
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The pool of therapeutic peptides could not be larger: They are obtained from unicellular, multicellular and multicellular organisms, or come from recombinant or chemical libraries. The number of these biomolecules is confusingly large, and the number of their derivatives is even greater.
What is Peptides for Recovery
“As a rule, peptide active ingredients have many weak points,” says Tanja Weil, a chemist with many years of pharmaceutical experience. The assessment of the Ulm researcher is shared by many. The list of disadvantages of peptide active ingredients is long.
Shortcoming number one: Peptides usually have to be injected because they are quickly broken down by proteolytic enzymes in the digestive tract. Shortcoming number two: peptides have a short half-life because they are also broken down quickly in the cells. Shortcoming number three: the liver and kidneys quickly remove peptides from the circulation. Shortcoming number four: Because of their hydrophilic properties, they hardly pass any physiological hurdles. Shortcoming number five: their pronounced conformational flexibility sometimes leads to a lack of selectivity, activates different target structures and leads to side effects.
Because of their shorter half-lives, few peptides accumulate in tissues, thereby reducing hazards arising from complications from their degradation products. Compared to the larger proteins and antibodies, peptides can penetrate deeper into the tissue. In addition, they are generally less immunogenic than recombinant proteins and antibodies. In addition, there are lower production costs, higher activity, greater stability (storage at room temperature). Many therapeutic peptides are derived from natural proteins or polypeptides and often interact with membrane proteins. Usually small amounts are sufficient to activate or deactivate the target receptors. Few peptide antagonists that inhibit the ligand-receptor interaction have hit the market so far.
Does Peptides for Recovery Work?
Around a dozen peptide molecules are in late clinical stages. The approved peptide active ingredients cover a wide range of indications and are administered intravenously, subcutaneously, inhalatively and even orally (linaclotid). The majority of the approximately 120 test substances are aimed at the indications of oncology and infection. More than half of the pipeline peptides have a single target, with a tenth targeting microbes. The most frequently activated target structures are the membrane proteins, which are located in the outer cell membrane and conduct stimuli from the outside into the cell’s interior, especially G-protein-coupled receptors (almost 40 percent, according to Kaspar/Reichert). Many of the peptides currently in phase II have been linked to other molecules, such as PEG or lipids.
Stabilize and functionalize Peptides for Recovery
We can use it to synthesize peptides that nature cannot produce in this way and that have improved properties,” summarizes the Ulm chemist. One inevitably thinks of Lego building blocks when Tanja Weil begins to explain why peptides are now so well suited for ‘pharmaceutical development’ Example Cysteine This sulfur-containing, naturally occurring amino acid can form disulfide bridges that stabilize the molecule. Cysteine, if incorporated at a specific site, could also link peptides together. With this, according to Weil, coupling reactions could be optimized in such a way that, in the end, a functional protein could even be produced in the test tube. Complete production of an enzyme in a test tube is still a dream. But the way there seems to be mapped out.
Optimization is progressing
According to Weil, some optimization strategies have now reached a certain level of maturity. Animal experiments are now being carried out with encapsulated peptide active ingredients that are intended to pass through the gastrointestinal tract. The bioavailability of peptides can be extended by transporting them using nanovehicles such as mesoporous silica particles, or by attaching polymers such as polyethylene glycol groups to the peptide drug (PEGylation). These polymers are known for their low adsorption to plasma proteins, which keeps the drugs stable in the bloodstream for longer and allows them to target cellular surface receptors.
Research also promises a stabilizing effect by adding groups to the biomolecules that are not quickly recognized by enzymes. The breakdown of peptide active ingredients by digestive enzymes can be slowed down, for example, by incorporating D-amino acids instead of L-amino acids. Recently, the Münch, Kirchhoff and Weil working groups identified and characterized a peptide that forms visible aggregates that significantly improve the transport of viruses into cells and could be of interest for gene therapy, for example. “There are some promising approaches here,” not least in Ulm, where research is more advanced than with oral availability, says Tanja Weil.
New stars among the biologicals?
Biologicals such as peptides are gaining importance because of their high specificity and biological activity, since many small molecules fail because of toxic metabolites and unintended interactions. In view of advanced optimization strategies, peptide active ingredients are now considered an attractive class of substances that can open up new indications in the semisynthetic area, including in the area of the CNS (Vlieghe, 54). Peptides are already being tested as anti-cancer and anti-inflammatory agents, as antibiotics and enzyme inhibitors in a variety of indications. Antimicrobial peptides are predicted to have a great future.
The search for active ingredients in nature is not a new idea; the search in human body fluids is new. That could be an advantage because “the problem is always the separation, even with small molecules, their isolation and purification,” says Weil. Logically, endogenous peptides have a different toxicological profile than exogenous substances extracted from sponges or cytotoxic substances from tree bark.
And it’s not just researchers in Ulm who believe that the degradome, the sum of proteins broken down by proteolytic enzymes, is neither biological waste nor a coincidence. The importance of this degradome is supported by the observation that the more than 500 proteases that cut these peptides from proteins can be altered under pathological conditions. In addition, there is growing evidence that some of these larger protein cleavage products show specific and sometimes highly unexpected activity against human pathogens.
It is highly probable that many important peptidic immune modulators and effectors are hidden in the human organism. A dozen therapeutically interesting peptides with antimicrobial and anti- or proviral activity fished from human peptide libraries are already known (Münch, Ständker, 15). By no means every peptide obtained from body fluids is suitable for development as a therapeutic agent. The people of Ulm also value the knowledge gained as a benefit. Her hope is to increase our understanding of how cells are controlled and how they enter cells, and in the process possibly discover completely new mechanisms of action or defense in the body.