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

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Τίτλος: Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
Συγγραφείς: Coassolo L; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., B Danneskiold-Samsøe N; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA., Nguyen Q; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Wiggenhorn A; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Chemistry, Stanford University, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Zhao M; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Wang DC; Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Toomer D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Lone J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Wei Y; Departments of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA., Patel A; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Liparulo I; Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA., Kavi D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Wat LW; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Reghupaty SC; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Kim JJ; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA., Asemi T; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Bielczyk-Maczynska E; The Hormel Institute, University of Minnesota, Austin, MN, USA., Li VL; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Chemistry, Stanford University, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Moya-Garzon MD; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Krentz NAJ; Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA.; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Stahl A; Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA., Chou DH; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.; Division of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA., Luo L; Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Svensson KJ; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. katrinjs@stanford.edu.; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA. katrinjs@stanford.edu.; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. katrinjs@stanford.edu.
Πηγή: Nature [Nature] 2025 May; Vol. 641 (8061), pp. 192-201. Date of Electronic Publication: 2025 Mar 05.
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Imprint Name(s): Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
Ιατρικοί όροι (MeSH): Obesity*/drug therapy , Obesity*/metabolism , Anti-Obesity Agents*/pharmacology , Anti-Obesity Agents*/metabolism , Anti-Obesity Agents*/chemistry , Peptides*/pharmacology , Peptides*/metabolism , Peptides*/chemistry , Proteolysis*, Proprotein Convertase 1/metabolism ; Eating/drug effects ; Body Weight/drug effects ; Leptin/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Receptor, Melanocortin, Type 4/metabolism ; Glucagon-Like Peptide-1 Receptor/metabolism ; Peptide Fragments/metabolism ; Peptide Fragments/pharmacology ; Peptide Fragments/chemistry ; Peptide Hormones/metabolism ; Animals ; Mice ; Humans ; Male ; Swine ; Female ; Mice, Inbred C57BL ; Drug Discovery
Περίληψη: 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.
(© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)
Competing Interests: Competing interests: K.J.S. and L.C. are named inventors on patents regarding BRP peptides for metabolic disorders. K.J.S. is a co-founder of Merrifield Therapeutics. All other authors declare no competing interests.
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Grant Information: K99 AR081618 United States AR NIAMS NIH HHS; R01 DK125260 United States DK NIDDK NIH HHS; T32 GM113854 United States GM NIGMS NIH HHS; 23IPA1042031 United States AHA American Heart Association-American Stroke Association; P30 DK116074 United States DK NIDDK NIH HHS; S10 OD030452 United States OD NIH HHS
Substance Nomenclature: 0 (Anti-Obesity Agents)
EC 3.4.21.93 (Proprotein Convertase 1)
0 (Leptin)
0 (Proto-Oncogene Proteins c-fos)
0 (Peptides)
0 (Receptor, Melanocortin, Type 4)
0 (Glucagon-Like Peptide-1 Receptor)
0 (Peptide Fragments)
0 (Peptide Hormones)
Entry Date(s): Date Created: 20250305 Date Completed: 20250501 Latest Revision: 20260502
Update Code: 20261018
PubMed Central ID: PMC12043402
DOI: 10.1038/s41586-025-08683-y
PMID: 40044869
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1476-4687
DOI:10.1038/s41586-025-08683-y