Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity

Shmuel Hess, Yaniv Linde, Oded Ovadia, Eli Safrai, Deborah E. Shalev, Avi Swed, Efrat Halbfinger, Tair Lapidot, Ilan Winkler, Yael Gabinet, Avi Faier, Dana Yarden, Zhimin Xiang, Federico P. Portillo, Carrie Haskell-Luevano, Chaim Gilon, Amnon Hoffman

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (αMSH) 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.

Original languageEnglish (US)
Pages (from-to)1026-1034
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number4
DOIs
StatePublished - Feb 28 2008

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