AI Helps Stanford Scientists Discover "Natural Ozempic" Without the Usual Side Effects
核心洞察
Stanford researchers used an AI algorithm called Peptide Predictor to identify BRP, a 12-amino-acid peptide that reduced food intake by up to 50% in mice and minipigs.
Unlike semaglutide, BRP appears to act specifically in the hypothalamus, potentially avoiding widespread gastrointestinal and other side effects associated with current GLP-1 (搜索)-based therapies.
In a 14-day study, obese mice treated with daily BRP injections lost an average of 3 grams, primarily from body fat, while control animals gained 3 grams, and also showed improved glucose and insulin tolerance.
Stanford University scientists have harnessed artificial intelligence to discover a naturally occurring peptide that suppresses appetite with a potency rivaling semaglutide (Ozempic) but through a more targeted mechanism that may spare patients from the gastrointestinal side effects that plague current therapies. The findings were published March 5 in Nature.
The molecule, named BRP (BRINP2-related-peptide) (搜索), is a tiny fragment composed of just 12 amino acids. Despite its small size, it produced the strongest neuronal activation signal in the team's initial screening — a tenfold increase over untreated controls, surpassing even GLP-1 (搜索)'s threefold response.
"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," said senior author Katrin Svensson, PhD, assistant professor of pathology at Stanford. "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."
AI-Driven Discovery from the Human Proteome
The breakthrough relied on a custom-built algorithm called Peptide Predictor, which systematically scanned all 20,000 human protein-coding genes for cleavage sites recognized by prohormone convertase 1/3 (搜索) — an enzyme previously linked to obesity (搜索) in humans and known to generate GLP-1 (搜索) from its precursor.
The algorithm narrowed the search to 373 prohormones predicted to yield 2,683 distinct peptides. From this pool, the researchers selected 100 candidates most likely to affect brain function and tested them on neuron-like cells. BRP emerged as the standout.
"The algorithm was absolutely key to our findings," Svensson said.
Preclinical Efficacy Across Species
In lean mice and minipigs — the latter chosen for their closer resemblance to human metabolism — a single intramuscular injection of BRP before feeding reduced food intake during the subsequent hour by as much as 50%.
In a 14-day study of obese mice, daily BRP injections produced an average weight loss of 3 grams, with nearly all reduction attributable to body fat. Control animals gained approximately 3 grams over the same period. Treated mice also demonstrated improved glucose and insulin tolerance, suggesting metabolic benefits beyond weight reduction alone.
A Cleaner Side-Effect Profile
Behavioral assessments revealed no meaningful differences between BRP-treated and untreated animals in movement, water consumption, anxiety-like behavior, or fecal production. The absence of changes in fecal output is particularly notable given that semaglutide slows gastrointestinal transit and commonly causes constipation. The researchers also observed no nausea-related responses or significant muscle loss.
Additional analyses confirmed that BRP operates through metabolic and neuronal pathways distinct from those engaged by GLP-1 (搜索) or semaglutide, reinforcing the hypothesis of a more focused mechanism of action.
The Road to Human Trials
Svensson has co-founded Merrifield Therapeutics (搜索), which plans to initiate clinical trials in humans in the near future. However, several scientific questions remain unresolved.
The team has not yet identified the cell-surface receptor to which BRP binds — a critical step for fully elucidating its mechanism. They are also working to map the downstream signaling cascade triggered by receptor engagement.
A further challenge is pharmacokinetic: small peptides are typically degraded rapidly in the body. The researchers are exploring strategies to extend BRP's half-life to enable practical dosing schedules.
"The lack of effective drugs to treat obesity (搜索) 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."
The study was led by senior research scientist Laetitia Coassolo, PhD, with contributions from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Funding was provided by 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, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance. Svensson and Coassolo are inventors on patents covering BRP peptides for metabolic disorders.