Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity.
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.
Hess
Shmuel
S
Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Linde
Yaniv
Y
Ovadia
Oded
O
Safrai
Eli
E
Shalev
Deborah E
DE
Swed
Avi
A
Halbfinger
Efrat
E
Lapidot
Tair
T
Winkler
Ilan
I
Gabinet
Yael
Y
Faier
Avi
A
Yarden
Dana
D
Xiang
Zhimin
Z
Portillo
Federico P
FP
Haskell-Luevano
Carrie
C
Gilon
Chaim
C
Hoffman
Amnon
A
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
D019440:Anti-Obesity Agents; D008024:Ligands; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4