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

  • Nature. 2025 Mar 5. doi: 10.1038/s41586-025-08683-y.
Laetitia Coassolo  1  2  3 ,  Niels B Danneskiold-Samsøe  1  2 ,  Quennie Nguyen  1 ,  Amanda Wiggenhorn  1  4  5 ,  Meng Zhao  1  2  3 ,  David Cheng-Hao Wang  6 ,  David Toomer  1 ,  Jameel Lone  1  2  3 ,  Yichao Wei  7 ,  Aayan Patel  1 ,  Irene Liparulo  8 ,  Deniz Kavi  1 ,  Lianna W Wat  1  2  3 ,  Saranya Chidambaranathan Reghupaty  1  2  3 ,  Julie Jae Kim  1  2 ,  Tina Asemi  1 ,  Ewa Bielczyk-Maczynska  9 ,  Veronica L Li  1  4  5 ,  Maria Dolores Moya-Garzon  1  5 ,  Nicole A J Krentz  10  11 ,  Andreas Stahl  8 ,  Danny Hung-Chieh Chou  2  10 ,  Liqun Luo  6 ,  Katrin J Svensson  12  13  14
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 4. Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 5. Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 6. Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • 7. Departments of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
  • 8. Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA.
  • 9. The Hormel Institute, University of Minnesota, Austin, MN, USA.
  • 10. Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 11. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • 12. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 13. Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 14. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
PMID: 40044869 DOI: 10.1038/s41586-025-08683-y
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.

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