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 discovery, leveraging advanced artificial intelligence, could represent a significant leap forward in the ongoing battle against obesity and metabolic disorders, offering a potentially more targeted and tolerable therapeutic option.
A Novel Approach to Appetite Regulation
The newly identified molecule, designated as BRP (BRINP2-related-peptide), operates through a distinct yet related metabolic pathway compared to semaglutide. Crucially, it appears to activate a separate group of neurons in the brain, a key distinction that researchers believe could lead to a more precise and refined method for controlling appetite and body weight.
"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."
The hypothalamus, a small but vital region situated deep within the brain, plays a pivotal role in orchestrating a wide array of bodily functions including hunger, thirst, body temperature, hormone activity, and overall energy expenditure. By focusing its action primarily on this area, BRP holds the promise of influencing appetite and metabolism without triggering the cascade of systemic effects often associated with broader-acting drugs.
This promising development has led Dr. Svensson to co-found a company poised to initiate clinical trials of BRP in human subjects in the near future, marking a significant transition from laboratory discovery to potential clinical application. The groundbreaking research was published on March 5th in the prestigious scientific journal Nature, with Dr. Laetitia Coassolo, a senior research scientist at Stanford Medicine, serving as the lead author of the study.
The Power of Artificial Intelligence in Peptide Discovery
The serendipitous identification of BRP was heavily reliant on the sophisticated application of artificial intelligence (AI). This cutting-edge technology enabled the research team to navigate the immense complexity of proteins belonging to a class known as prohormones.
Prohormones are essentially inactive precursor molecules that do not exert their biological functions until they are enzymatically cleaved into smaller fragments known as peptides. Some of these peptides then act as potent hormones, carrying crucial signals that influence a multitude of complex processes within the brain and throughout the body, including metabolism and appetite regulation.
A single prohormone can be processed in numerous ways, yielding a vast array of potential peptides. The challenge for researchers has historically been the difficulty in pinpointing the biologically significant ones. Genuine peptide hormones are relatively rare and can easily be obscured by the large numbers of ordinary fragments generated during normal protein processing and degradation.
While traditional laboratory methods have been instrumental in isolating and identifying peptides, they often generate an overwhelming volume of data. This necessitates the painstaking process of sorting through hundreds of thousands, if not millions, of molecular candidates to uncover the few that possess meaningful biological effects.
Strategic Search for Metabolic Signals
The Stanford team strategically focused their investigation on an enzyme called prohormone convertase 1/3 (PC1/3). This enzyme is known to cleave prohormones at specific amino acid sequences, and it has a documented link to obesity in human populations.
One of the well-established peptides produced through the action of PC1/3 is glucagon-like peptide 1 (GLP-1). GLP-1 is a key regulator of hunger and blood sugar levels, and it forms the basis for the mechanism of action of semaglutide and similar drugs. The researchers hypothesized that PC1/3 might also be responsible for generating other peptides with similar or complementary roles in energy balance and appetite control.
To systematically explore this hypothesis, the team turned to artificial intelligence. Instead of relying solely on laborious manual extraction of proteins and peptides from biological tissues, followed by time-consuming analytical techniques such as mass spectrometry, the researchers developed an innovative computer algorithm they named "Peptide Predictor."
Peptide Predictor: Accelerating Discovery
Peptide Predictor was designed to systematically scan all 20,000 human protein-coding genes, searching for the specific types of cleavage sites where prohormone convertases, like PC1/3, typically interact with proteins. This initial broad search was then further refined. 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 potential cleavage sites.
This rigorous filtering process dramatically reduced the number of candidate prohormones from the entire human genome to a more manageable group of 373. "The algorithm was absolutely key to our findings," Dr. Svensson emphasized, highlighting the transformative impact of AI on their research workflow.
Peptide Predictor further estimated that PC1/3 could potentially generate 2,683 distinct peptides from these 373 prohormones. With this significantly reduced and more tractable dataset, Dr. Coassolo and Dr. Svensson then concentrated their efforts on sequences that showed the highest probability of influencing brain function, particularly those related to appetite and metabolism.
They ultimately selected 100 candidate peptides, including the known hormone GLP-1, for experimental testing. Their initial validation involved assessing whether these peptides could stimulate neuron-like cells cultured in the laboratory.
A Small Peptide, a Profound Impact
As anticipated, GLP-1 demonstrated a potent ability to activate the neuronal cells, significantly increasing their activity to three times the level observed in untreated control cells. However, the researchers were astonished by the response elicited by a much smaller peptide. This peptide, comprised of a mere 12 amino acids, produced an even more dramatic effect, increasing neuronal activity tenfold compared to the control group.
This remarkable peptide was named 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. A molecule composed of only 12 amino acids is exceptionally small in comparison to most full-length proteins, yet BRP exhibited the most potent response in these initial cell-based assays.
Promising Results in Pre-Clinical Animal Models
Building on these compelling in vitro findings, the research team advanced their studies to pre-clinical animal models. They tested BRP in both lean mice and, notably, minipigs. Minipigs were chosen for their metabolic and eating patterns, which are considered to more closely mirror those of humans than mice, offering a more translational model.
In these studies, an intramuscular injection of BRP administered shortly before feeding led to a substantial reduction in food intake. Within the following hour, food consumption was decreased by as much as 50% in both species.
Furthermore, the researchers conducted a 14-day study involving obese mice. Daily injections of BRP resulted in an average weight loss of 3 grams among the treated animals, with the vast majority of this reduction attributed to body fat loss. In contrast, the control group of mice experienced an average weight gain of approximately 3 grams over the same period.
Beyond weight management, the BRP-treated mice also exhibited improved glucose and insulin tolerance. These physiological markers are critical indicators of how effectively the body regulates blood sugar and responds to insulin, the hormone essential for facilitating glucose uptake into cells.
Addressing Key Side Effects
A significant area of focus for the researchers was to assess whether BRP might mitigate some of the well-documented side effects associated with existing weight-loss medications. Behavioral testing revealed no meaningful differences between the BRP-treated animals and the untreated controls in several key areas, including movement, water consumption, anxiety-like behaviors, and fecal production.
The absence of any significant alteration in fecal production was particularly noteworthy. This is a crucial observation because semaglutide and similar drugs are known to slow down digestion, frequently leading to constipation, a common and often bothersome side effect. Additionally, the researchers did not observe any responses indicative of nausea or significant muscle loss, which have been associated with some other weight-loss treatments.
Further detailed measurements of brain activity and overall body function corroborated the unique mechanism of BRP. These analyses indicated that BRP operates through distinct metabolic and neuronal pathways compared to those activated by GLP-1 or semaglutide. This suggests that BRP may achieve its appetite-suppressing effects through a more focused biological route, although these findings are currently confined to animal studies.
Charting the Path Forward: Human Trials and Future Challenges
The Stanford team is actively pursuing several critical avenues of research to pave the way for human clinical trials. A primary objective is to precisely identify the cell-surface receptors to which BRP binds. Receptors act as molecular docking stations, receiving signals from hormones, drugs, and other chemical messengers. Understanding which specific receptor BRP interacts with will be instrumental in deciphering its precise mechanism of action in altering appetite and metabolism.
The researchers also aim to fully map the cascade of events that unfolds after BRP successfully binds to its target receptor. This detailed understanding will be crucial for optimizing its therapeutic potential and for identifying any potential off-target effects.
Another significant challenge lies in addressing the duration of BRP’s action. Small peptides, by their nature, can be rapidly broken down by the body, which can limit their therapeutic effects. The team is actively investigating strategies to enhance the stability and longevity of BRP in the body. This will be essential for developing a practical dosing regimen for human use.
"The lack of effective drugs to treat obesity in humans has been a problem for decades," Dr. 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 collaborative nature of this research is underscored by contributions from researchers at the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. The study received significant funding from various prestigious sources, including the National Institutes of Health (with multiple grant numbers), 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 pertaining to BRP peptides for metabolic disorders, and Dr. Svensson is a co-founder of Merrifield Therapeutics, a company that will likely be instrumental in the future development and commercialization of this promising new molecule. The journey from laboratory discovery to a widely available therapeutic is long and complex, but the initial findings surrounding BRP offer a compelling beacon of hope in the ongoing quest for more effective and well-tolerated treatments for obesity and related metabolic conditions.
