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

• 成果类型: Article
• 署名作者: Coassolo, Laetitia; Danneskiold-Samsoe, Niels B.; Nguyen, Quennie; Wiggenhorn, Amanda; Zhao, Meng; Wang, David Cheng-Hao; Toomer, David; Lone, Jameel; Wei, Yichao; Patel, Aayan; Liparulo, Irene; Kavi, Deniz; Wat, Lianna W.; Reghupaty, Saranya Chidambaranathan; Kim, Julie Jae; Asemi, Tina; Bielczyk-Maczynska, Ewa; Li, Veronica L.; Moya-Garzon, Maria Dolores; Krentz, Nicole A. J.; Stahl, Andreas; Chou, Danny Hung-Chieh; Luo, Liqun; Svensson, Katrin J.
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute; Stanford University; Stanford University; University of California System; University of California Berkeley; University of Minnesota System; Stanford University; University of British Columbia
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2466
• DOI: 10.1038/s41586-025-08683-y
• 发表日期: 2025-05-01
• 关键词: mass-spectrometry; neuropeptide-y; messenger-rna; polypeptide; physiology; glucagon; plasma; rat; identification; transcription

摘要

Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1)1,2. However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.