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

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.

A New Frontier in Weight Management: The Discovery of BRP

In a significant breakthrough that could reshape the landscape of obesity treatment, scientists at Stanford Medicine have pinpointed a naturally occurring molecule, dubbed BRP, that demonstrates a remarkable ability to curb appetite and promote weight loss in preclinical studies. This discovery, published on March 5th in the prestigious journal Nature, offers a potential new therapeutic avenue that mimics the efficacy of widely recognized drugs like semaglutide (Ozempic, Wegovy) but with a potentially more favorable side effect profile.

The molecule’s distinct mechanism of action, targeting a specific region of the brain responsible for appetite regulation, sets it apart from existing treatments. Unlike semaglutide, which acts on receptors found throughout the body, BRP appears to concentrate its effects on the hypothalamus, a crucial area for managing hunger and metabolism. This targeted approach could translate into a more precise and potentially less burdensome therapeutic experience for individuals seeking to manage their weight.

Unraveling the Mystery: The Role of Artificial Intelligence

The journey to BRP’s discovery was heavily reliant on the power of artificial intelligence. Researchers leveraged advanced computational tools to sift through vast datasets of proteins, specifically prohormones, which serve as inactive precursors to biologically active peptides. Prohormones undergo enzymatic cleavage to release these smaller peptide fragments, many of which act as signaling molecules influencing a myriad of bodily functions, including metabolism and appetite.

The challenge in identifying these critical peptides lies in their relative rarity and their tendency to be masked within a deluge of ordinary protein fragments generated during normal cellular processes. Traditional laboratory methods, while effective, can be time-consuming and generate overwhelming amounts of data. To overcome this hurdle, the Stanford team developed an innovative computer algorithm named "Peptide Predictor."

This AI-powered tool meticulously scanned all 20,000 human protein-coding genes, searching for specific enzymatic cleavage sites typically targeted by prohormone convertase 1/3 (PC1/3). This particular enzyme has garnered attention for its known link to obesity in humans, making it a logical focus for the research. The algorithm further refined the search by prioritizing genes that produce proteins secreted outside the cell – a common characteristic of hormones – and that possessed at least four potential cleavage sites. This sophisticated filtering process dramatically narrowed the field of investigation from thousands of genes to a manageable 373 prohormones.

A Targeted Approach to Appetite Control

Katrin Svensson, PhD, an assistant professor of pathology at Stanford Medicine and senior author of the study, explained the significance of this targeted approach. "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," Svensson noted. "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, a small but vital region deep within the brain, plays a central role in regulating fundamental physiological processes such as hunger, thirst, body temperature, hormone secretion, and energy expenditure. By focusing on this area, BRP holds the promise of influencing appetite and metabolic balance with a reduced likelihood of the off-target effects that can accompany systemic drug action.

From Lab to Life: Preclinical Successes and Future Directions

The research team, led by senior research scientist Laetitia Coassolo, PhD, first tested the peptides identified by Peptide Predictor on neuron-like cells in laboratory settings. As anticipated, the well-known appetite regulator glucagon-like peptide 1 (GLP-1), which semaglutide emulates, significantly boosted neuronal activity. However, one particular peptide, BRP, a mere 12 amino acids long, elicited an even more profound response, increasing neuronal activity tenfold. This discovery underscored BRP’s potent signaling capabilities.

The subsequent phase of the research involved testing BRP in both lean and obese animal models, including minipigs, which share metabolic and eating patterns more closely with humans than rodents do. In these studies, an intramuscular injection of BRP administered before feeding led to a remarkable reduction in food intake, by as much as 50%, within an hour in both species.

Over a 14-day period, obese mice treated with daily BRP injections experienced an average weight loss of 3 grams, with the reduction primarily attributed to body fat. Concurrently, the control group of mice gained approximately 3 grams, highlighting BRP’s significant impact on energy balance. Beyond weight loss, the treated mice also exhibited improved glucose and insulin tolerance, crucial indicators of effective metabolic regulation.

Perhaps most encouragingly, the preclinical trials revealed a notable absence of common side effects associated with current weight-loss medications. Behavioral assessments in treated animals showed no significant differences in movement, water consumption, anxiety levels, or fecal production compared to their untreated counterparts. This is particularly significant as semaglutide is known to cause constipation due to its effect on digestive motility. Furthermore, researchers did not observe any signs of nausea or substantial muscle loss, which have been reported with some existing weight management therapies. These findings suggest that BRP may engage distinct metabolic and neuronal pathways, offering a potentially safer and more tolerable option.

Navigating the Path Forward: Challenges and Opportunities

Despite the promising preclinical results, the journey from laboratory discovery to human application involves several critical steps and challenges. The Stanford team is actively working to identify the specific cell-surface receptors to which BRP binds. Understanding this molecular interaction is key to fully elucidating how BRP influences appetite and metabolism.

Another crucial area of investigation is the duration of BRP’s action. Small peptides are often rapidly metabolized by the body, which can limit their therapeutic window. Researchers are exploring methods to enhance BRP’s stability and prolong its effects, aiming for a dosing schedule that is practical for widespread clinical use.

The translation of these findings into human therapies is a high priority for Dr. Svensson. She has co-founded a company that is preparing to initiate clinical trials of BRP in humans in the near future. "The lack of effective drugs to treat obesity in humans has been a problem for decades," Svensson stated. "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."

The potential implications of BRP extend beyond individual weight management. The development of a more targeted and potentially safer alternative to existing obesity medications could significantly improve patient outcomes and reduce the burden of obesity-related diseases, such as type 2 diabetes and cardiovascular disease. The global obesity epidemic, affecting over one billion people worldwide according to the World Health Organization, presents a pressing public health challenge, making innovations like BRP critically important.

Broader Context and Scientific Collaboration

The discovery of BRP is a testament to the power of interdisciplinary research and technological advancement. The integration of artificial intelligence into biological discovery represents a paradigm shift, enabling scientists to tackle complex biological questions with unprecedented efficiency and insight. This project benefited from the collaborative efforts of researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia, underscoring the global nature of scientific progress.

Funding for this groundbreaking research was provided by a consortium of esteemed organizations, including the National Institutes of Health, 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. Dr. Svensson and Dr. Coassolo are listed as inventors on patents related to BRP peptides for metabolic disorders, and Dr. Svensson is a co-founder of Merrifield Therapeutics, the company poised to advance BRP into human clinical trials.

As the scientific community awaits the results of human trials, the discovery of BRP marks a significant step forward in the quest for effective and well-tolerated obesity treatments, offering a beacon of hope for millions grappling with this complex health issue.