A small protein isolated from beetroot is able to block the activity of an enzyme called prolyl oligopeptidase (POP), which breaks down certain hormones and signaling molecules, and is thought to control the body’s inflammatory responses.
According to the researchers, the discovery of this plant-derived protein may make possible new therapies targeting POP, which is increasingly being explored as a target for neurodegenerative and inflammatory disorders like multiple sclerosis (MS) and Alzheimer’s disease.
The study, “Discovery of a Beetroot Protease Inhibitor to Identify and Classify Plant-Derived Cystine Knot Peptides,” published in the Journal of Natural Products.
Many species of plants evolved to develop mechanisms that protect them from pests and herbivores. One such mechanism uses the production of small proteins, or peptides, that are highly resistant to pests and harsh environmental conditions.
Peptide protease inhibitors are a class of peptides that protect plants from bacteria, viruses, and insects by destroying the enzymes these pests use to digest plant tissue. This particular class of peptides is also promising as peptide-based therapy candidates, due to their cysteine bonds that sometimes form “knot-like structures” that make them highly stable in acid environments, as well as highly resilient to degradation.
Of note, cysteine is one of the 23 amino acids that are the building blocks of proteins; when two cysteine residues interact with each other, they are able to make highly stable disulfide bonds that sometimes intertwine to form a knot.
Although many sub-classes of these peptide protease inhibitors have been identified, “there is still a limited understanding of how certain protease inhibitors are distributed within the plant kingdom.”
Researchers at the Center for Physiology and Pharmacology with the Medical University of Vienna and their colleagues described how they discovered a new peptide protease inhibitor from a species of beetroot called Beta vulgaris. This inhibitor shows therapeutic potential based not only on its knot-like structure, but also on its ability to block the activity of the POP enzyme.
While screening B. vulgaris leaves and pulp extracts for peptide protease inhibitors with disulfide bonds, researchers discovered a small peptide they later named Beta vulgaris trypsin inhibitor I, or bevuTI-I for short.
After using mass spectrometry to determine the exact amino acid sequence of bevuTI-I, the team looked for other previously described peptides with similar sequences that could provide clues on the function and properties of the new peptide.
These analyses indicated bevuTI-I’s sequence was similar to trypsin inhibitors found in spinach (S. oleracea) and in the four o’clock plant (Mirabilis jalapa), which belonged to a subfamily of compounds known as knottin trypsin inhibitors. These trypsin inhibitors have a unique “knot-like structure” made up of three disulfide bonds intertwined with each other. (Trypsin is an enzyme that breaks down proteins.)
Additional analyses showed that bevuTI-I could inhibit both trypsin, as expected based on its similarity with other trypsin inhibitors, and POP. Like trypsin, POP is also able to break down proteins and other signaling molecules in the body. This enzyme has also started to be investigated as a potential target for treating certain inflammatory and neurodegenerative disorders due to its ability to control inflammatory responses.
“This means that, in future studies, this group of plant peptides called ‘knottins’, such as those found in beetroot, could potentially provide a drug candidate for treating these diseases,” Christian Gruber, PhD, an associate professor at the center and the study’s senior author, said in a press release.
Researchers also discovered the new bevuTI-I peptide can be found in commercially available beetroot juice, albeit in very small amounts. They added that would be unreasonable to assume the regular consumption of beetroot would protect against inflammatory and neurodegenerative diseases, as at this point it is still unknown if the peptide can be absorbed through the gastrointestinal tract.
“Our study highlights great potential of plant protease inhibitors isolated from beetroot and other related plant species as a valuable source for peptide-based drug discovery for targets involved in diseases such as cancer, neurodegenerative disorders, and immune system related diseases,” the researchers wrote.
The team now plans to further explore the properties certain natural compounds have in developing treatment candidates.
“We are searching through large databases containing genetic information of plants and animals, decoding new types of peptide molecules and studying their structure, aiming to test them pharmacologically on enzymes or cellular receptors … and finally analyzing them in the disease models,” Gruber said.
These researchers successfully used this approach a few years ago to create a treatment candidate for MS, T20K, based on a natural plant peptide called cyclotide. T20K is now licensed to Cyxone, and has shown promising efficacy at lowering the production of pro-inflammatory signaling molecules in MS animal models.
It was also found to be safe and well tolerated in healthy volunteers participating in a Phase 1 trial. A potential Phase 2 trial assessing T20K in MS patients is now being planned.
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