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. This groundbreaking discovery, detailed in the prestigious journal Nature, could herald a new era in the treatment of obesity and metabolic disorders, offering a potentially more targeted and tolerable approach to weight management.

The newly identified molecule, dubbed BRP (BRINP2-related-peptide), operates through a distinct yet related metabolic pathway compared to semaglutide. Its unique mechanism involves activating a separate group of neurons within the brain, a crucial difference that researchers believe could lead to a more precise and effective tool for controlling appetite and body weight without the widespread systemic effects often associated with current therapeutic agents.

A More Targeted Approach to Appetite Control

Assistant Professor of Pathology Katrin Svensson, PhD, a senior author on the study, explained the significance of BRP’s localized action. "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," Svensson stated. "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 critical region nestled deep within the brain, serves as the body’s central regulator for a multitude of essential functions, including hunger, thirst, body temperature, hormone activity, and energy expenditure. By concentrating its effects primarily within this area, BRP may offer a means to modulate appetite and metabolism with a reduced risk of off-target effects in other bodily systems. This specificity is a key factor driving excitement around its potential therapeutic applications.

This promising development has not gone unnoticed by the scientific and investment communities. Professor Svensson has co-founded a company poised to advance BRP into human clinical trials in the near future, a testament to the molecule’s perceived potential and the robust preclinical data supporting its efficacy and safety profile. The journey from laboratory discovery to potential therapeutic intervention is often long and arduous, but the initial findings for BRP suggest a more accelerated path forward.

The research, published on March 5 in Nature, represents a significant collaborative effort. Senior research scientist Laetitia Coassolo, PhD, served as the lead author of the study, spearheading the intricate experimental design and data analysis. Their work builds upon decades of research into the complex hormonal and neural pathways that govern energy balance and body weight.

Artificial Intelligence Unlocks Hidden Peptides

The discovery of BRP was heavily reliant on the sophisticated application of artificial intelligence (AI). This technological leap enabled researchers to efficiently sift through vast datasets of proteins, specifically focusing on a class known as prohormones.

Prohormones are essentially inactive precursor molecules. Their biological function is only realized when specific enzymes cleave them into smaller, active fragments called peptides. These peptides then act as hormones, carrying crucial signals that influence a wide array of physiological processes, including metabolism, appetite regulation, and other complex functions within the brain and throughout the body.

The challenge lies in the sheer diversity of these cleavage products. A single prohormone can be processed in multiple ways, yielding a multitude of peptides. Identifying the truly biologically significant ones is a formidable task, as genuine peptide hormones are relatively rare and can be easily obscured by a vast number of ordinary fragments generated during normal protein processing and degradation.

Historically, traditional laboratory methods have been employed to isolate and identify peptides. However, these methods often generate enormous quantities of data, requiring researchers to manually sift through hundreds of thousands of molecules in search of those with meaningful biological effects. This labor-intensive process can be both time-consuming and prone to human error.

Searching for New Metabolic Signals with Precision

The Stanford team strategically focused their investigation on an enzyme called prohormone convertase 1/3 (PC1/3). This particular enzyme is known to cleave prohormones at specific amino acid sequences and has previously been implicated in human obesity, making it a prime candidate for further exploration in the context of appetite regulation.

One of the well-established peptides produced through the action of PC1/3 is glucagon-like peptide 1 (GLP-1). GLP-1 plays a vital role in regulating hunger and blood sugar levels, and its mechanism of action is the basis for semaglutide and other related drugs. The researchers hypothesized that PC1/3 might also be responsible for generating other, as-yet-undiscovered peptides that could profoundly influence energy balance and appetite.

To test this hypothesis and navigate the complexity of peptide identification, the researchers turned to artificial intelligence. Instead of relying solely on conventional, data-intensive laboratory extraction and mass spectrometry techniques, they developed a novel computer algorithm named Peptide Predictor.

Peptide Predictor: A New Frontier in Peptide Discovery

The Peptide Predictor algorithm was designed to systematically search all 20,000 human protein-coding genes. Its primary function was to identify potential sites where prohormone convertases, like PC1/3, typically cleave proteins. This initial broad search was then refined through a series of targeted filters. The researchers narrowed their focus to genes that produce proteins secreted outside the cell – a common characteristic of hormones – and that contained at least four plausible cleavage sites.

This meticulous filtering process significantly reduced the number of candidate prohormones for investigation, bringing the manageable group down to 373. "The algorithm was absolutely key to our findings," Professor Svensson emphasized, highlighting the transformative impact of AI on their research capabilities.

Peptide Predictor further estimated that PC1/3 could generate an astonishing 2,683 distinct peptides from these 373 prohormones. From this extensive list, Coassolo and Svensson then prioritized sequences that showed the highest likelihood of impacting brain function related to appetite and metabolism. They selected 100 peptides, including the known player GLP-1, for experimental validation.

A Tiny Peptide with an Outsized Effect

In their initial laboratory tests, the researchers assessed the ability of these selected peptides to stimulate neuron-like cells cultured in vitro. As anticipated, GLP-1 demonstrated a strong stimulatory effect, increasing neuronal activity by three times the level observed in untreated control cells.

However, one much smaller peptide produced an even more remarkable response. This molecule, BRP, composed of only 12 amino acids, triggered a tenfold increase in neuronal activity compared to the control group. This disproportionate effect from such a small molecule underscored its potent biological activity.

The researchers named this peptide BRP, derived from its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2. Amino acids are the fundamental building blocks of proteins and peptides, and a molecule consisting of just 12 amino acids is considered extremely small relative to most full-length proteins. Yet, BRP’s initial cellular assays indicated a powerful influence on neuronal signaling.

Preclinical Studies Reveal Significant Weight Reduction and Metabolic Improvements

Building on these encouraging in vitro results, the Stanford team proceeded to test BRP in animal models. They utilized both lean mice and minipigs, the latter chosen for their metabolic and eating patterns that more closely mirror those of humans than rodent models.

In an intramuscular injection administered prior to feeding, BRP demonstrated a significant reduction in food intake. Within an hour of injection, both mice and minipigs consumed up to 50% less food compared to their untreated counterparts. This immediate and substantial impact on appetite was a key finding.

Further studies involved administering daily BRP injections to obese mice over a 14-day period. The results were striking: the treated animals experienced an average weight loss of 3 grams, with virtually all of this reduction attributed to a decrease in body fat. In contrast, the control group of obese mice gained approximately 3 grams during the same timeframe, highlighting BRP’s efficacy in promoting fat loss and counteracting weight gain.

Beyond weight reduction, BRP also showed positive effects on glucose and insulin tolerance in the obese mice. These physiological markers are critical indicators of metabolic health, reflecting the body’s ability to efficiently regulate blood sugar and respond to insulin, the hormone essential for moving glucose from the bloodstream into cells for energy. Improved glucose and insulin tolerance suggest that BRP may not only aid in weight management but also contribute to better overall metabolic function.

Absence of Common Side Effects Signals Potential for Improved Tolerability

A crucial aspect of the preclinical research involved detailed behavioral and physiological assessments to evaluate potential side effects. Notably, treated and untreated animals exhibited no meaningful differences in measures of movement, water consumption, anxiety-like behavior, or fecal production.

The lack of impact on fecal production is particularly noteworthy. Constipation is a common and often distressing side effect associated with semaglutide, stemming from its effect of slowing gastrointestinal transit. The absence of this side effect in BRP-treated animals suggests a potential advantage in patient tolerability.

Furthermore, the researchers did not observe any signs of nausea-related responses, which are frequently reported with GLP-1 receptor agonists. Equally significant was the absence of substantial muscle loss, another concern sometimes associated with rapid weight loss achieved through pharmacological interventions.

Additional analyses of brain activity and broader body function confirmed that BRP engages metabolic and neuronal pathways that are distinct from those activated by GLP-1 or semaglutide. This corroborates the hypothesis that BRP’s more focused mechanism of action could translate to a more favorable side effect profile in humans. While these findings are currently limited to animal studies, they provide a strong foundation for optimism regarding BRP’s therapeutic potential.

Navigating the Path to Human Clinical Trials

Despite the promising preclinical results, researchers are diligently working to fully elucidate BRP’s mechanism of action. A key next step involves identifying the specific cell-surface receptors to which BRP binds. Receptors act as molecular docking stations, receiving signals from hormones, drugs, and other chemical messengers to initiate cellular responses. Pinpointing BRP’s target receptor is paramount for understanding precisely how it influences appetite and metabolism.

The team also aims to map the complete cascade of molecular events that occur after BRP binds to its receptor. This detailed understanding will provide invaluable insights into the intricate signaling pathways involved and could reveal further therapeutic targets or potential interactions.

Another significant challenge for peptide-based therapeutics is their inherent stability in the body. Small peptides are often rapidly broken down by enzymes, which can limit the duration of their therapeutic effects. The researchers are actively investigating methods to enhance BRP’s stability and prolong its action. Developing a formulation that allows for a more practical dosing schedule, such as once-daily or less frequent administration, will be crucial for its eventual clinical utility.

"The lack of effective drugs to treat obesity in humans has been a problem for decades," Professor Svensson remarked, underscoring the persistent unmet medical need in this area. "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 journey from laboratory discovery to a widely available treatment is a complex and rigorously regulated process. The successful completion of preclinical studies marks a significant milestone, paving the way for the crucial next phase: human clinical trials. These trials will systematically evaluate BRP’s safety, tolerability, and efficacy in human participants, providing the definitive data needed to determine its therapeutic value.

This research was a multidisciplinary endeavor, with contributions from researchers at the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. The study received substantial funding from various sources, including 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. These diverse funding streams underscore the broad interest and support for innovative approaches to metabolic health.

In recognition of the potential impact of their findings, Professor Svensson and Dr. Coassolo are listed as inventors on patents pertaining to BRP peptides for the treatment of metabolic disorders. Furthermore, Professor Svensson’s role as a co-founder of Merrifield Therapeutics signifies a direct commitment to advancing this promising molecule towards clinical application, potentially offering a new beacon of hope for millions struggling with obesity and related health conditions. The development of BRP represents a compelling example of how cutting-edge AI, combined with fundamental biological research, can accelerate the discovery of novel therapeutic agents with the potential to revolutionize healthcare.