Stanford Medicine scientists have identified a naturally occurring molecule that shares some similarities in its mechanism of action with Semaglutide (Ozempic) for reducing appetite and body weight. Unlike existing therapies, animal experiments indicate that this molecule does not cause common side effects, including nausea, constipation, and significant muscle loss.
BRP (the newly described molecule) acts as an alternative, related metabolic mechanism that affects different neuronal groups in the brain. This mode of action offers a more selective and precise approach to weight control, with potentially greater safety.
Semaglutide affects receptors that are localized not only in the brain, but are also widespread in the digestive system, pancreas, and other tissues, explains Dr. Katrin Svensson, assistant professor of pathology.
This wide range of receptor activity is responsible for the many systemic effects of Ozempic, including slowed gastric emptying and lowering of blood sugar levels. However, the available data indicate that BRP has a significantly more selective effect, primarily on the hypothalamus (the central regulator of appetite and metabolic processes).
Dr. Svensson is one of the founders of a company that is preparing to launch human clinical trials of this molecule in the near future. This author’s research was published on March 5 in the prestigious journal Nature, while Dr. Leatita Coassolo, senior researcher, is listed as the lead author of the study.
This research would not be feasible without the inclusion of artificial intelligence, which enabled the efficient analysis and selection of dozens of proteins from the prohormone category. Prohormones are biologically inactive precursors that can only turn into smaller peptide fragments after enzymatic breakdown.
After the process is completed, individual molecules can take over the role of hormones. These hormone peptides play a key role in regulating complex physiological processes, including the control of energy metabolism in the brain and peripheral organs.
A special feature of prohormones is their ability to be cleaved in multiple ways, yielding a large number of potentially functional peptides. However, using traditional protein isolation techniques, it is extremely difficult to identify and separate peptide hormones, present in small amounts, from a complex biological mixture, which contains, among other things, numerous products of protein breakdown and processing.
The research team focused on prohormone convertase 1/3, an enzyme that breaks down prohormones at well-defined amino acid sites and is associated with body weight regulation and obesity in humans.
Among the peptides produced by this process is glucagon-like peptide-1 (GLP-1), a key regulator of appetite and blood sugar levels. The mechanism of action of Semaglutide is based on imitating the effect of GLP-1.
To expand understanding of the role of peptides controlling energy metabolism, researchers have used artificial intelligence to identify additional bioactive peptides, thereby uncovering new regulatory mechanisms and potential therapeutic targets.
Peptide Predictor
Instead of lengthy, technically demanding procedures for manual isolation of proteins and peptides from tissues, and the application of mass spectrometry to identify numerous molecules, the researchers developed a specialized computer algorithm called Peptide Predictor. This algorithm was used to systematically identify characteristic prohormone cleavage sites within a set of approximately 20.000 protein-coding genes in the human genome.
To further narrow the selection, the scientists focused only on genes that code for proteins intended for secretion from the cell (a feature characteristic of hormone molecules), and on those that possess at least four potential enzymatic processing sites. This approach enabled reducing the initial analyses to 373 prohormones, yielding a practical set of candidates for testing biological functions.
“Until now, no tested substance has come close to Semaglutide in its ability to reduce appetite and body weight. Scientists are very excited to test whether this molecule is safe and effective in humans,” Svensson said.
“The algorithm was a key to our discovery,” she added. Peptide Predictor predicted that prohormone convertase 1/3 would produce 2.683 unique peptides from 373 target proteins. Coassolo and Svensson spotted sequences that might be biologically active in the brain and tested 100 peptides, including GLP-1, on neurons grown in the laboratory.
As expected, GLP-1 significantly increased cell activity – three times more than in control samples. However, a small peptide of only 12 amino acids stimulated their activity by 10 times that of the control. The researchers named it BRP, after its parent prohormone BPM/retinoic acid inducible neural specific 2 (BRINP2), i.e., BRINP2-related peptide.
When researchers tested BRP on animal models lean mice and minipigs) that mimic human metabolism and eating patterns better than ordinary mice – they noticed that a single intramuscular injection before a meal could significantly reduce food intake in the next hour by up to 50%.
Obese mice that received daily injections of BRP for two weeks lost an average of 3 grams, exclusively of fat tissue, while control mice gained about 3 grams during the same period. In addition, the animals showed improved glucose and insulin tolerance.
Behavioral analyses showed no changes in locomotion, water intake, anxiety level, or fecal excretion in treated animals. Further studies of brain and metabolic activity revealed that BRP may activate distinct neuronal and metabolic pathways, distinct from those stimulated by GLP-1 or Semaglutide.
Researchers are actively seeking receptors on cell surfaces to which BRP binds, thereby elucidating in more detail the pathways through which the peptide can act. The effects of BRP and the potential for a longer duration in the body are also being studied, which would enable simpler, more practical dosing if it is shown that the peptide successfully regulates body weight in humans.
“For centuries, we have struggled to find effective drugs to treat obesity in humans,” says Svensson. “Nothing we’ve tested so far can match Semaglutide for its ability to reduce appetite and body weight. We’re now very excited to learn whether BRP is safe and effective in humans. In addition to Svensson, scientists from the University of Minnesota and the University of British Columbia participated in this research.
Research was supported by the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618, and GM113854), the SPARK Translational Research Program at Stanford, Stanford Bio-X, the Stanford Maternal and Child Health Research Institute, the American Heart Association, Stanford Medicine Dean’s Fellowships, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance. Svensson and Coassolo are also inventors on patents related to BRP peptides for the treatment of metabolic disorders, and Dr. Svensson is a co-founder of Merrifield Therapeutic.
