Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide

5 years ago

Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide

Shiro Takekawa, Hideki Hirabayashi, Tomoko Asakawa, Kouta Matsumiya, Tetsuya Ohtaki, Hiroshi Inooka, Hisashi Fujita, Yoko Kanematsu-Yamaki, Taiji Asami, Katsuko Dote, Tomoko Kaisho, Naoki Nishizawa, Junichi Sakamoto, Taisuke Mochida, Hiroaki Nagai

Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00330

DOI: 10.1021/acs.jmedchem.7b00330