BRINP2
The protein BMP/retinoic acid-inducible neural-specific protein 2 (BRINP2) is a brain-specific, secreted protein recently identified as the precursor of a novel appetite-regulating peptide. Although originally annotated without a defined biological function, BRINP2 has gained renewed attention due to its unexpected role in the regulation of energy balance.
As the prevalence of obesity and type 2 diabetes continues to rise globally, there is an increasing urgency to develop therapeutic strategies beyond the well-established GLP-1 receptor pathway. While GLP-1 receptor agonists have demonstrated clinical success, they are often associated with gastrointestinal side effects, reduced tolerability, and limited long-term efficacy. Therefore, identifying alternative mechanisms to safely regulate appetite is a key priority in current drug development efforts.
Non-peptide drugs targeting GLP-1 are also being developed. Discover some of small molecules currently in clinical trials and their mechanism of action in our Protein of the Month featuring GLP-1.
One promising approach has recently emerged with the discovery of endogenous peptide hormones as potential therapeutic targets. These peptides are attractive due to their natural role in regulating energy homeostasis and their typically low concentrations in the body, which may reduce the risk of systemic toxicity and off-target effects.
Using computational drug discovery methods, researchers developed Peptide Predictor, an AI-based tool designed to identify cleavable bioactive peptides within the proteome. By focusing on secreted proteins, the team discovered an anorexigenic peptide derived from BRINP2, the BRINP2-related peptide (BRP).
BRP is a 12-amino-acid long stretch (THRILRRLFNLC) corresponding to residues 386–397 of BRINP2, flanked by KK and KR motifs that are recognized and cleaved by the prohormone convertase PCSK1 (prohormone convertase 1/3). In vivo experiments demonstrated that BRP robustly suppressed appetite in mice and pigs, validating its physiological relevance.
Structural insights into BRINP2 and BRP
While no experimental high-resolution structure of BRINP2 or BRP currently exists, AlphaFold predictions suggest that BRINP2 is largely a disordered protein, consistent with the flexible nature often seen in secreted regulatory proteins. Within the predicted structure, the BRP peptide region is one of the few segments showing a more organized conformation, forming an alpha-helical structure.
Further structural analysis revealed that the predicted alpha-helical stretch of BRP is exposed on the surface of the precursor protein, making it accessible to cleavage by prohormone convertases.
Alanine-scanning mutagenesis of the BRP sequence identified Leu8 as critical for function. Mutation at this position reduced cellular FOS activation, suggesting that specific hydrophobic interactions, possibly enhancing peptide-receptor binding or membrane association, are essential for its bioactivity.
Biological role of BRINP2-derived BRP
Further biological studies confirmed that BRP acts independently of classical metabolic receptors, including the GLP-1 receptor, MC4R, and leptin receptor. Instead, BRP activates an unidentified Gαs-coupled GPCR, leading to stimulation of the cAMP–PKA–CREB–FOS pathway in neurons. BRP induced a stronger Fos response in the hypothalamus compared to GLP-1, without causing nausea or aversion behaviors commonly seen with GLP-1-based therapies.
Notably, BRP's effects on food intake were dose-dependent, and its anorexigenic effects were maintained in diet-induced obese mouse models, demonstrating therapeutic relevance across metabolic states.
Therapeutic potential of targeting the BRINP2–BRP pathway
While synthetic analogs of BRP are not yet in clinical development, this discovery highlights a new class of peptides that could complement or replace current strategies combating obesity and type 2 diabetes.
Structural predictions suggest that even largely disordered proteins can hide bioactive elements with significant therapeutic potential. As research progresses toward receptor identification and analog optimization, BRP stands as a promising candidate for developing safer, more effective anti-obesity therapies. In a landscape increasingly seeking alternatives beyond GLP-1 receptor agonists, BRINP2 represents a new frontier in metabolic disease drug discovery.
Reference:
Coassolo L, B Danneskiold-Samsøe N, Nguyen Q, Wiggenhorn A, Zhao M, Wang DC, Toomer D, Lone J, Wei Y, Patel A, Liparulo I, Kavi D, Wat LW, Reghupaty SC, Kim JJ, Asemi T, Bielczyk-Maczynska E, Li VL, Moya-Garzon MD, Krentz NAJ, Stahl A, Chou DH, Luo L, Svensson KJ. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide. Nature. 2025 May;641(8061):192-201. doi: 10.1038/s41586-025-08683-y. Epub 2025 Mar 5. PMID: 40044869; PMCID: PMC12043402.