title: Rational design of dual peptides targeting ghrelin and Y2 receptors to regulate food intake and body weight.
abstract: Ghrelin and Y2 receptors play a central role in appetite regulation inducing opposite effects. The Y2 receptor induces satiety, while the ghrelin receptor promotes hunger and weight gain. However, the food regulating system is tightly controlled by interconnected pathways where redundancies can lead to poor efficacy and drug tolerance when addressing a single molecule. We developed a multitarget strategy to synthesize dual peptides simultaneously inhibiting the ghrelin receptor and stimulating the Y2 receptor. Dual peptides showed dual activity in vitro, and one compound induced a slight diminution of food intake in a rodent model of obesity. In addition, stability studies in rats revealed different behaviors between the dual peptide and its corresponding monomers. The Y2 receptor agonist was unstable in blood, while the dual peptide showed an intermediate stability compared to that of the highly stable ghrelin receptor inverse agonist.
authors.affiliation: †Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany.
authors.forename: Tom-Marten
authors.initials: TM
authors.lastname: Kilian
authors.affiliation: ‡Integrated Research and Treatment Center Adiposity Diseases (IFB), Core Unit "Animal Models", Universität Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: §Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, P.O. Box 510119, 01314 Dresden, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: †Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Els-Heindl
authors.affiliation: †Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Babilon
authors.affiliation: ∥CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Clément-Ziza
authors.affiliation: ⊥B CUBE-Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstrasse 18, 01307 Dresden, Germany.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany.
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
authors.affiliation: †Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Brüderstrasse 34, 04103 Leipzig, Germany.|⊥B CUBE-Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstrasse 18, 01307 Dresden, Germany.
authors.forename: Constance
authors.initials: C
authors.lastname: Chollet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects*; D019556:COS Cells; D002522:Chlorocebus aethiops; D015195:Drug Design; D004435:Eating / Q000187:drug effects*; D005260:Female; D054439:Ghrelin; D006801:Humans; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D054440:Receptors, Ghrelin / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: D019440:Anti-Obesity Agents; D054439:Ghrelin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D054440:Receptors, Ghrelin; C429983:intestinal y2 receptor