title: Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity.
abstract: The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Hess
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Linde
authors.forename: Oded
authors.initials: O
authors.lastname: Ovadia
authors.forename: Eli
authors.initials: E
authors.lastname: Safrai
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Shalev
authors.forename: Avi
authors.initials: A
authors.lastname: Swed
authors.forename: Efrat
authors.initials: E
authors.lastname: Halbfinger
authors.forename: Tair
authors.initials: T
authors.lastname: Lapidot
authors.forename: Ilan
authors.initials: I
authors.lastname: Winkler
authors.forename: Yael
authors.initials: Y
authors.lastname: Gabinet
authors.forename: Avi
authors.initials: A
authors.lastname: Faier
authors.forename: Dana
authors.initials: D
authors.lastname: Yarden
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Federico P
authors.initials: FP
authors.lastname: Portillo
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D019440:Anti-Obesity Agents; D008024:Ligands; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4