AI helps Stanford scientists discover “natural Ozempic” without the usual side effects - ScienceDaily

Stanford Medicine researchers have identified a naturally occurring molecule that may suppress appetite and reduce body weight in a way that resembles semaglutide, the active ingredient in Ozempic. In animal studies, the molecule also appeared to avoid several problems associated with the drug, including nausea, constipation and substantial muscle loss. The molecule, known as BRP, works through a different but related metabolic pathway and activates a separate group of neurons in the brain. That distinction could make it a more precise tool for controlling appetite and body weight. A More Targeted Approach to Appetite Control "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," said assistant professor of pathology Katrin Svensson, PhD. "That's why Ozempic has widespread effects including slowing the movement of food through the digestive tract and lowering blood sugar levels. In contrast, BRP appears to act specifically in the hypothalamus, which controls appetite and metabolism." The hypothalamus is a small region deep within the brain that helps regulate hunger, body temperature, hormone activity and energy use. Because BRP appears to act mainly in this area, it may influence appetite without producing as many effects elsewhere in the body. Svensson has co-founded a company that plans to begin clinical trials of the molecule in humans in the near future. Svensson is the senior author of the research, which was published March 5 in Nature. Senior research scientist Laetitia Coassolo, PhD, is the lead author of the study. Artificial Intelligence Reveals Hidden Peptides The discovery depended heavily on artificial intelligence, which allowed the researchers to search through proteins belonging to a group known as prohormones. Prohormones are inactive precursor molecules. They do not perform their final biological function until enzymes cut them into smaller fragments called peptides. Some of these peptides then act as hormones, carrying signals that influence metabolism, appetite and other complex processes in the brain and throughout the body. A single prohormone can be cut in several different ways, producing many possible peptides. Finding the biologically important ones is difficult because genuine peptide hormones are relatively rare and can be buried among large numbers of ordinary fragments created during normal protein processing and breakdown. Traditional laboratory methods can isolate and identify peptides, but the process can produce enormous amounts of data. Researchers may need to sort through hundreds of thousands of molecules to find the few that have meaningful effects. The team concentrated on an enzyme called prohormone convertase 1/3. This enzyme cuts prohormones at specific amino acid sequences and has previously been linked to obesity in humans. One of the peptides produced through this process is glucagon-like peptide 1, or GLP-1. GLP-1 helps regulate hunger and blood sugar, and semaglutide works by copying its effects in the body. The researchers reasoned that the same enzyme might produce other peptides that influence energy balance and appetite. To find them, they turned to artificial intelligence. Rather than manually extracting proteins and peptides from tissues and then using methods such as mass spectrometry to identify huge numbers of molecules, the researchers created a computer algorithm called Peptide Predictor. The program searched all 20,000 human protein-coding genes for the types of sites where prohormone convertases typically cut proteins. The researchers then narrowed the search to genes that produce proteins secreted outside the cell, a common feature of hormones, and that contained at least four possible cleavage sites. That process reduced the field to 373 prohormones, giving the team a much more manageable group to investigate. "The algorithm was absolutely key to our findings," Svensson said. Peptide Predictor estimated that prohormone convertase 1/3 could produce 2,683 distinct peptides from those 373 proteins. Coassolo and Svensson then focused on sequences that seemed most likely to affect the brain. They selected 100 peptides, including GLP-1, and tested whether they could stimulate neuron-like cells grown in the laboratory. As expected, GLP-1 strongly activated the neuronal cells, increasing their activity to three times the level seen in untreated control cells. One much smaller peptide produced an even more dramatic response. Made from only 12 amino acids, it increased neuronal activity tenfold compared with controls. The researchers named the peptide BRP after its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2 (BRINP2-related-peptide). Amino acids are the basic building blocks of proteins and peptides. A molecule containing only 12 of them is extremely small compared with most full-sized proteins, yet BRP produced the strongest response in the initial cell tests. The researchers next tested BRP in lean mice and minipigs (which more closely mirror human metabolism and eating patterns than mice do). An intramuscular injection given before feeding reduced food intake during the following hour by as much as 50% in both species. The team also gave daily BRP injections to obese mice for 14 days. On average, the treated animals lost 3 grams, with nearly all of the reduction coming from body fat. Mice in the control group gained about 3 grams over the same period. The treated mice also showed improved glucose and insulin tolerance. These measures reflect how effectively the body regulates blood sugar and responds to insulin, the hormone that helps move glucose from the bloodstream into cells. Behavioral testing found no meaningful differences between treated and untreated animals in movement, water consumption, anxiety-like behavior, or fecal production. The absence of changes in fecal production was especially notable because semaglutide can slow digestion and cause constipation. The researchers also did not observe the nausea-related responses or major muscle loss associated with some existing weight loss treatments. Additional measurements of brain activity and body function showed that BRP acts through metabolic and neuronal pathways that differ from those activated by GLP-1 or semaglutide. Those findings suggest that BRP may reduce appetite through a more focused biological route, although the results remain limited to animals. The researchers are now working to identify the cell-surface receptors that attach to BRP. Receptors are molecular structures that receive signals from hormones, drugs, and other chemical messengers. Determining which receptor BRP uses will help scientists understand exactly how the peptide changes appetite and metabolism. The team also wants to map the full sequence of events that occurs after BRP binds to its target. Another challenge is duration. Small peptides are often broken down quickly in the body, which can shorten their effects. The researchers are investigating ways to make BRP last longer so that, if it eventually works in people, it could be administered on a more practical schedule. "The lack of effective drugs to treat obesity in humans has been a problem for decades," Svensson said. "Nothing we've tested before has compared to semaglutide's ability to decrease appetite and body weight. We are very eager to learn if it is safe and effective in humans." Researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia contributed to the work. The study was funded 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, a Stanford Medicine Dean's Fellowship Award, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance. Svensson and Coassolo are inventors on patents regarding BRP peptides for metabolic disorders. Svensson is a co-founder of Merrifield Therapeutics. Materials provided by Stanford Medicine. Note: Content may be edited for style and length. 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