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The global obesity problem is becoming increasingly severe, with projections indicating that by 2050, 80% of the population in the USA will face weight management challenges. GLP-1 class drugs (especially semaglutide and tirzepatide) occupy a significant position in the market, but their side effects limit clinical application. The Stanford team used an AI program called "Peptide Predictor" to identify 373 potentially active proteins, and screened out 100 peptide molecules that may affect the appetite regulation center. Among these, a novel short peptide molecule, BRINP2-related peptide (called BRP), has attracted attention due to its unique activity. Research shows that BRP activates specific neurons in the hypothalamus, triggering the cAMP-PKA-CREB-FOS signaling pathway, forming a completely new mechanism of neuromodulation. This mechanism not only allows BRP to demonstrate anti-obesity potential comparable to GLP-1 receptor agonists, but also shows significant advantages in avoiding the risk of side effects associated with traditional drugs. The relevant research findings were published in Nature.

BRINP2-Related Peptide: A New Star in the Field of Weight Loss

BRP consists of 12 amino acids and is produced by enzymatic cleavage from the BRINP2 protein. Researchers have successfully detected the presence of BRP in human cerebrospinal fluid samples and mouse brain tissues, suggesting that this molecule may serve as an important signaling mediator within the central nervous system, participating in the regulatory network of various physiological functions.

BRP(H-THRILRRLFNLC-NH2)

Structure of BRP

The research team found that BRP can directly act on key neurons regulating appetite - pro-opiomelanocortin (POMC) neurons - activating intracellular cAMP-PKA-CREB-FOS signaling cascades. Animal experimental data show that this mechanism can significantly inhibit the feeding behavior of experimental animals, reducing food intake by up to 50%. Unlike the multi-target metabolic regulation mode of GLP-1 receptor agonists, the action of BRP has high spatial specificity, with its main target concentrated in the hypothalamic region - a critical area in the brain responsible for regulating appetite and metabolism.

Experimental results indicate that GLP-1 peptides increase the expression level of Fos in the Neuroscreen-1 (NS-1) neuronal cell line by 3 times and in the β-cell line INS1 by 10 times, while BRP increases the expression of Fos in both cell lines by more than 10 times, demonstrating a stronger biological effect. Notably, due to the highly focused targets of BRP on the central nervous system, it avoids gastrointestinal disturbances and pancreatic function regulation similar to those caused by traditional weight loss drugs (such as GLP-1 agonists), thereby significantly reducing the risk of peripheral side effects such as nausea and constipation.

Highlights of BRP Preclinical Studies

***Effective Weight Loss*** Pharmacokinetic studies show that BRP reaches peak blood concentration within 1 minute after injection, followed by rapid distribution. In dose-response experiments, the 5 mg/kg dose group showed significantly reduced food intake, while the 20 mg/kg group nearly completely suppressed feeding behavior for up to 3 hours, demonstrating a clear dose-effect relationship. In mini-pigs, BRP injection prior to feeding reduced food intake by 50% within 1 hour. After 14 days of treatment, obese mice experienced a 4g reduction in fat mass, whereas control mice gained 3g.

***Metabolic Improvement*** BRP significantly improved glucose tolerance and insulin sensitivity in mice, while simultaneously reducing fasting blood glucose and insulin levels, and alleviating hepatic lipid accumulation. The weights of subcutaneous white adipose tissue, brown adipose tissue, and liver were all reduced. Notably, BRP selectively reduced fat mass without affecting lean body mass, achieving effects comparable to those of the GLP-1 receptor agonist liraglutide at a dose of 100 µg/kg.

***Behavioral Safety*** During treatment, BRP did not induce anxiety-like behaviors, changes in locomotor activity, water intake, or sucrose preference in mice. No nausea or anorexia was observed.

***Structural Dependence*** Through amino acid substitution experiments, it was confirmed that leucine at position 8 is a critical active site for BRP-induced cAMP activation, CREB S133 phosphorylation, and Fos expression—substitution at this position resulted in complete loss of function. Additionally, C-terminal amidation of BRP is essential for its biological activity, as non-amidated BRP exhibited no activity in vitro. These findings provide clear directions for drug optimization.

BRP Weight Loss Effect

Future Prospects: Industrial Breakthroughs of Neuropeptide Drugs and AI-Driven Drug Discovery

The mechanism of action of BRP significantly differs from known appetite-regulating peptide hormones such as GLP-1, leptin, and melanocortin 4 receptor (MC4R)-mediated pathways. By employing a novel "hypothalamic-centric" regulatory model, BRP opens up an innovative approach for the treatment of obesity. The signaling pathways it triggers work by reshaping the hypothalamic appetite-metabolism regulatory network, precisely regulating the dynamic balance between energy intake and expenditure. This "hypothalamic-centric" regulatory model provides a new paradigm for obesity treatment — one that does not rely on peripheral hormone systems but instead breaks through traditional targets to directly intervene in the central nervous system's perception of energy requirements.

Activation of CREB-FOS Pathway by BRP

Merrifield Therapeutics is advancing BRP into clinical trial stages, with hopes of it becoming the first side-effect-free neuropeptide weight loss drug. This offers new options for patients with limited treatment choices and also signals the broad prospects of neuropeptide drugs. Peptide hormones, as a class of endogenous signaling molecules composed of fewer than a hundred amino acids, play crucial roles in key physiological processes such as energy homeostasis regulation. To date, twelve peptide hormones closely related to the regulation of feeding behavior have been clearly identified, including neuropeptide Y, insulin, leptin, and GLP-1.

Notably, prohormone convertase 1/3 (PCSK1/3) serves as a critical processing enzyme involved in the maturation process of various metabolism-related peptide hormones, for example, precisely cleaving proglucagon into fully biologically active GLP-1 molecules. The "Peptide Predictor" algorithm developed by the research team, through analyzing PCSK1/3 cleavage sites, screened out 373 potential prohormones from over 20,000 human genes and predicted 2,683 unique peptides, most of which originate from the central nervous system and liver tissues. Among these predicted peptides, 21%-23% are potentially significantly bioactive. Through in vitro experiments, researchers identified BRP as exhibiting high biological activity. This "computation-first" strategy has significantly shortened the drug discovery cycle, and combined with AI-driven technology, neuropeptide drugs may demonstrate even greater potential in areas such as Alzheimer's disease and Parkinson's disease in the future.

Principle of the Peptide Predictor

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