TOKYO —

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, powered by artificial intelligence, opens a new frontier in the search for effective obesity treatments and metabolic disorder management.

The newly identified molecule, dubbed BRP (BRINP2-related-peptide), operates through a distinct yet related metabolic pathway, activating a separate set of neurons in the brain. This crucial difference could position BRP as a more precise and potentially better-tolerated tool for controlling appetite and managing body weight compared to existing medications.

A More Targeted Approach to Appetite Regulation

The distinction in how BRP functions is central to its potential therapeutic advantage. Semaglutide, a highly successful weight-loss and diabetes drug, targets receptors for glucagon-like peptide 1 (GLP-1), which are present not only in the brain but also throughout the gut, pancreas, and other tissues. This widespread distribution accounts for semaglutide’s multifaceted effects, including slowing the digestive process and lowering blood sugar levels, but also contributes to its common side effects such as nausea, constipation, and, in some cases, significant muscle mass reduction.

In contrast, early research suggests that BRP acts more specifically within the hypothalamus, a small but critical region deep within the brain. The hypothalamus is the master regulator of numerous vital bodily functions, including hunger, thirst, body temperature, hormone activity, and overall energy expenditure. By seemingly focusing its action on this appetite and metabolism control center, BRP may offer a way to influence food intake and body weight without eliciting the broader systemic effects that lead to gastrointestinal distress and other adverse reactions observed with GLP-1 receptor agonists.

"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," explained Katrin Svensson, PhD, an assistant professor of pathology at Stanford Medicine and senior author of the study. "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."

This targeted action is a significant development in the field. The global obesity epidemic, affecting over 40% of the adult population in the United States alone according to the Centers for Disease Control and Prevention (CDC), has spurred intense research into novel therapeutic strategies. While drugs like semaglutide have demonstrated remarkable efficacy, their associated side effect profiles limit their applicability for some individuals. The prospect of a molecule that can achieve similar weight loss results with a more favorable tolerability profile is highly anticipated.

Dr. Svensson has co-founded a company poised to advance BRP into human clinical trials in the near future, marking a critical step from laboratory discovery to potential patient benefit. The research detailing these findings was published on March 5th in the prestigious journal Nature, with senior research scientist Laetitia Coassolo, PhD, serving as the lead author.

Artificial Intelligence: The Engine Behind Peptide Discovery

The serendipitous discovery of BRP was not a matter of chance but a testament to the power of advanced computational tools. The researchers heavily leveraged artificial intelligence (AI) to navigate the complex landscape of prohormones, a class of inactive precursor molecules that require enzymatic cleavage to yield active peptides.

Prohormones are essentially biological blueprints that, when acted upon by specific enzymes, are processed into smaller fragments known as peptides. These peptides can function as hormones, carrying crucial signals that orchestrate a wide array of physiological processes, including metabolism, appetite regulation, and numerous other complex functions within the brain and the rest of the body. The challenge lies in the sheer number of potential peptides that can be generated from a single prohormone, as a single precursor can be cut in multiple ways, leading to a vast array of fragments. Identifying the biologically significant peptide hormones among this multitude of ordinary byproducts of protein processing and breakdown is an arduous task.

Traditional laboratory methods, while capable of isolating and identifying peptides, often generate enormous datasets. Researchers might have to meticulously sift through hundreds of thousands of molecules to pinpoint the rare few that exert meaningful biological effects. This manual, data-intensive process can be time-consuming and resource-prohibitive.

Charting New Metabolic Signals with AI

To overcome these limitations, the Stanford team focused their investigation on a specific enzyme, prohormone convertase 1/3 (PC1/3). This enzyme plays a pivotal role in cleaving prohormones at particular amino acid sequences. Its link to metabolic regulation is well-established, with previous human studies implicating its dysfunction in obesity.

One of the well-known peptides generated by PC1/3 is glucagon-like peptide 1 (GLP-1). As mentioned, GLP-1 is instrumental in regulating hunger and blood sugar levels, and its mechanism of action is mimicked by semaglutide. The researchers hypothesized that PC1/3 might be responsible for producing other, as yet undiscovered, peptides with significant roles in energy balance and appetite control.

Peptide Predictor: A Novel Algorithm for Discovery

To systematically search for these potential new metabolic signals, the researchers developed a sophisticated AI-powered computer algorithm named "Peptide Predictor." This innovative tool allowed them to move beyond the laborious process of manually extracting and analyzing proteins and peptides from tissues, which typically involves techniques like mass spectrometry.

Instead of a brute-force approach, Peptide Predictor was designed to scan all approximately 20,000 human protein-coding genes. It specifically searched for the characteristic amino acid sequences that are recognized and cut by prohormone convertases like PC1/3. This initial AI-driven scan narrowed the vast genomic landscape to a more manageable subset of genes.

Further refinement of the search criteria focused on genes producing proteins that are secreted outside the cell – a common characteristic of hormones – and that contained at least four potential cleavage sites for PC1/3. This rigorous filtering process effectively reduced the number of candidate prohormones to a mere 373, providing the research team with a significantly more focused and investigable group.

"The algorithm was absolutely key to our findings," Dr. Svensson emphasized, underscoring the transformative impact of AI in accelerating scientific discovery.

From these 373 prohormones, Peptide Predictor estimated that PC1/3 could potentially produce an astonishing 2,683 distinct peptides. Dr. Coassolo and Dr. Svensson then applied their biological expertise to prioritize sequences that appeared most likely to influence brain function and, consequently, appetite and metabolism.

They selected a panel of 100 peptides, including GLP-1 as a positive control, and subjected them to rigorous in vitro testing. This testing involved assessing their ability to stimulate neuron-like cells cultured in the laboratory, providing an initial indication of their biological activity.

A Tiny Peptide, An Outsized Impact

The results of the cellular assays were striking. As anticipated, GLP-1 demonstrated significant activity, increasing the activity of the neuronal cells by threefold compared to untreated control cells. However, one particular peptide, BRP, a much smaller molecule composed of only 12 amino acids, elicited an even more profound response. This diminutive peptide amplified neuronal activity by a remarkable tenfold margin over the controls.

The researchers subsequently named this peptide BRP, derived from its parent prohormone, BPM/retinoic acid inducible neural specific 2 (BRINP2). Amino acids are the fundamental building blocks of proteins and peptides. The discovery that such a small peptide could exert such a potent effect was a significant breakthrough, defying initial expectations that larger molecules might be responsible for stronger signals.

Pre-clinical Efficacy: From Mice to Minipigs

Encouraged by these initial findings, the research team moved on to pre-clinical studies in animal models. To assess BRP’s efficacy in a more relevant context, they tested it in both lean mice and minipigs. Minipigs were chosen because their metabolic and eating patterns are considered to more closely mirror those of humans than laboratory mice, offering a more translatable model for potential human applications.

In these studies, a single intramuscular injection of BRP administered shortly before feeding led to a substantial reduction in food intake. Over the subsequent hour, treated animals consumed up to 50% less food in both species. This immediate and significant suppression of appetite demonstrated BRP’s potent effect on food consumption.

The team then conducted a longer-term study involving obese mice. For 14 consecutive days, daily BRP injections were administered to a group of obese mice. On average, these treated animals experienced a weight loss of 3 grams, with the reduction predominantly attributed to a decrease in body fat mass. In contrast, the control group of obese mice gained approximately 3 grams over the same period, highlighting BRP’s effectiveness in promoting weight loss and fat reduction.

Beyond weight loss, the BRP-treated obese mice also exhibited improvements in glucose and insulin tolerance. These metabolic markers are crucial indicators of how effectively the body regulates blood sugar and responds to insulin, the hormone essential for transporting glucose from the bloodstream into cells for energy. Improved glucose and insulin tolerance are key benefits for individuals with or at risk of developing type 2 diabetes.

Mitigating Side Effects: A Promising Early Indication

One of the most exciting aspects of the BRP discovery is its apparent lack of the common side effects associated with semaglutide and other weight-loss medications. Behavioral testing revealed no significant differences between treated and untreated animals in parameters such as movement, water consumption, anxiety-like behaviors, or fecal production.

The absence of altered fecal production is particularly noteworthy, as constipation is a frequent and often bothersome side effect of semaglutide due to its effect on slowing gastrointestinal transit. Furthermore, the researchers did not observe any signs indicative of nausea or substantial muscle loss, two other adverse effects that can impact patient adherence and quality of life with existing treatments.

Additional analyses of brain activity and overall body function confirmed that BRP operates through distinct metabolic and neuronal pathways compared to GLP-1 or semaglutide. These findings strongly suggest that BRP may achieve its appetite-suppressing effects through a more localized and specific biological route, although it is crucial to reiterate that these observations are currently limited to animal models.

Navigating the Path to Human Trials: Challenges and Prospects

While the pre-clinical data is highly encouraging, several critical questions remain as researchers prepare for human clinical trials. A primary focus is identifying the specific cell-surface receptors to which BRP binds. Understanding this molecular interaction is paramount for fully elucidating how the peptide influences appetite and metabolism at a cellular and systemic level.

The research team is also diligently working to map the complete cascade of events that occur after BRP engages with its target receptor. This detailed understanding will be vital for optimizing its therapeutic potential and predicting its effects in humans.

Another significant challenge for small peptides like BRP is their tendency to be rapidly broken down by the body, which can limit the duration of their therapeutic effects. Researchers are actively exploring strategies to enhance BRP’s stability and longevity, aiming to develop a formulation that can be administered on a practical and convenient schedule for patients.

"The lack of effective drugs to treat obesity in humans has been a problem for decades," Dr. Svensson stated, reflecting on the urgent need for new therapeutic options. "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 collaborative nature of this research is also worth noting. Contributions to this groundbreaking work came from researchers at the University of California, Berkeley; the University of Minnesota; and the University of British Columbia, underscoring the power of interdisciplinary and multi-institutional scientific endeavors.

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 highlight the significant scientific and societal interest in this area of research.

Both Dr. Svensson and Dr. Coassolo are listed as inventors on patents pertaining to BRP peptides for metabolic disorders, indicating a strong commitment to translating their scientific findings into tangible therapeutic solutions. Dr. Svensson also holds a co-founder position at Merrifield Therapeutics, a company dedicated to developing novel treatments for metabolic diseases. The journey from laboratory bench to bedside is long and complex, but the discovery of BRP represents a significant leap forward, offering renewed hope in the ongoing battle against obesity and related metabolic conditions.