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

Laetitia Coassolo, Niels B. Danneskiold-Samsøe, Quennie Nguyen, Amanda Wiggenhorn, Meng Zhao, David Cheng-Hao Wang, David Toomer, Jameel Lone, Yichao Wei, Aayan Patel, Irene Liparulo, Deniz Kavi, Lianna W. Wat, Saranya Chidambaranathan Reghupaty, Julie Jae Kim, Tina Asemi, Ewa Bielczyk-Maczynska, Veronica L. Li, Maria Dolores Moya-Garzon, Nicole A. J. Krentz, Andreas Stahl, Danny Hung-Chieh Chou, Liqun Luo and Katrin J. Svensson ()
Additional contact information
Laetitia Coassolo: Stanford University School of Medicine
Niels B. Danneskiold-Samsøe: Stanford University School of Medicine
Quennie Nguyen: Stanford University School of Medicine
Amanda Wiggenhorn: Stanford University School of Medicine
Meng Zhao: Stanford University School of Medicine
David Cheng-Hao Wang: Stanford University
David Toomer: Stanford University School of Medicine
Jameel Lone: Stanford University School of Medicine
Yichao Wei: Stanford University
Aayan Patel: Stanford University School of Medicine
Irene Liparulo: University of California Berkeley
Deniz Kavi: Stanford University School of Medicine
Lianna W. Wat: Stanford University School of Medicine
Saranya Chidambaranathan Reghupaty: Stanford University School of Medicine
Julie Jae Kim: Stanford University School of Medicine
Tina Asemi: Stanford University School of Medicine
Ewa Bielczyk-Maczynska: University of Minnesota
Veronica L. Li: Stanford University School of Medicine
Maria Dolores Moya-Garzon: Stanford University School of Medicine
Nicole A. J. Krentz: Stanford University
Andreas Stahl: University of California Berkeley
Danny Hung-Chieh Chou: Stanford University School of Medicine
Liqun Luo: Stanford University
Katrin J. Svensson: Stanford University School of Medicine

Nature, 2025, vol. 641, issue 8061, 192-201

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08683-y

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