MON-675 Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide

Abstract Disclosure: L. Coassolo: None. Peptide hormones, a class of pharmacologically active molecules, play a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (PCSK1/PCSK3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide-1 (GLP-1). However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. We developed Peptide Predictor, a computational drug discovery tool that systematically maps over 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified an orphan brain-derived 12-mer peptide, BRINP2-Related Peptide (BRP), which is endogenously circulating in human cerebrospinal fluid and cleaved by PCSK1. BRP exhibits potent properties in suppressing food intake and reversing obesity in both rodent and non-rodent species when administered pharmacologically. BRP acts as a signaling ligand in the central nervous system to regulate food intake without affecting insulin release, energy expenditure, locomotor activity, or anxiety-like behavior and without inducing nausea or aversion. Mechanistically, BRP administration triggers a central cAMP/PKA/CREB/Fos signaling pathway in POMC-negative hypothalamic neurons. Specifically, BRP induced Fos activation in the dorsomedial hypothalamic nucleus (DMH), preoptic hypothalamic nucleus, tuberal nucleus, and arcuate nucleus of the hypothalamus but did not activate Fos in the hindbrain or brainstem. In addition, BRP acts independently of leptin, glucagon-like receptor-1, and melanocortin-4 receptor indicating an independent pathway for control of appetite. Together, these data introduce Peptide Predictor as a drug discovery method to identify new bioactive peptides and establish pharmacological proof-of-concept that BRP may be useful for therapeutic modulation of appetite and body weight. Presentation: Monday, July 14, 2025