University of São Paulo: Small protein reduces sugar levels, generates patent and can be allied in the fight against diabetes

A small protein that originates from the cells of the human body can play a big role in controlling diabetes. In research with the participation of the Institute of Biomedical Sciences (ICB) at USP, scientists found that the peptide Ric4, synthesized from a protein produced by blood cells, increased insulin sensitivity and reduced blood glucose, that is, the level of sugar in the blood. Studies on the structure and properties of Ric4, carried out in animals, generated a patent that, in the future, could lead to medicines to treat diabetes, and that serve as an alternative to insulin therapy.

The results of the work are shown in an article published on the website of the scientific journal Pharmaceuticals, on December 16th. Type 2 diabetes occurs when the body develops resistance to insulin, which is responsible for processing sugar in the body and taking it to the cells, which increases the concentration of sugar in the bloodstream.

“A few years ago, our laboratory developed a test in an animal model that found alterations in a group of intracellular peptides (InPeps), which are small proteins produced inside cells, normally from larger proteins”, explains to Jornal da USP the Professor Emer Ferro, from the ICB, coordinator of the study. “The animals tested showed greater insulin sensitivity and, consequently, greater glucose uptake and reduced blood glucose. Our hypothesis was that this was due to changes in InPeps levels.”

Then, the researchers chemically synthesized four peptides in the laboratory, which were named Ric1, Ric2 and Ric3 and Ric4. “Ric 1 and Ric2 were identified in the gastrocnemius muscle (leg potato) and are derived from the troponin I protein; Ric3 was found in epididymal adipose tissue (in the pubic region), produced from the acyl-CoA binding protein, and Ric4 is derived from the alpha subunit of hemoglobin, a protein found in the blood”, describes the professor. “Our aim was to identify whether any of these peptides could pharmacologically reproduce the increased insulin sensitivity and reduced blood glucose observed in animals.”

“If that were to happen, we could identify a new peptide that could be used to treat patients diagnosed with pre-diabetes or type 2 diabetes, who have high glucose levels and do not respond to insulin,” says Ferro. “Cell viability tests were carried out in cell culture, evaluation of the effect of peptides on the expression levels of specific proteins (Western Blotting), enzyme stability, gene expression (PCR), glucose uptake in animal tissues and cultures. of mouse cells, and glucose tolerance and transport, in cells and animal models.”

The research found that two derivatives of the Ric4 peptide (Ric4-2 and Ric4-15) have hypoglycemic action, that is, they induce glucose uptake and reduce blood glucose in animals after oral administration. “The analyzes suggest that the peptide binds to the insulin receptor to induce glucose uptake, independently of insulin, the latter also a peptide, increasing its sensitivity”, points out the ICB professor. “Structural modifications of natural Ric4, which generated Ric4-2 and Ric4-15, reduced its degradation by digestive enzymes, without harming the pharmacological action. In summary, peptides such as Ric4 may exert an insulin-like action and may be useful in the treatment of patients with type 2 diabetes.”

According to Ferro, despite the biological and pharmacological significance, the possible clinical applications of Ric4 still deserve further investigation. “The study indicates that patients with pre-diabetes or type 2 diabetes, who have insulin-resistant hyperglycemia, could be treated with Ric4 or its analogues, Ric4-2 and Ric4-15. However, additional trials need to be carried out to assess the potency of the peptide in reducing blood glucose in patients with type 2 diabetes”, highlights Ferro. “Our work reinforces the view that peptides can retain their pharmacological activity after oral administration, ‘breaking’ the dogma that within the body they are immediately degraded by digestive enzymes.”

In addition to the publication of the article, a patent application for the peptide Ric4 was filed with the National Institute of Industrial Property (INPI) by the USP Innovation Agency (Auspin) and by INOVA, Unicamp’s Innovation Agency. “Although the application was filed in May 2018, no company has so far been interested in licensing the Ric4 patent for the development of an alternative drug to insulin for the treatment of type 2 diabetes”, concludes the professor.

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