title: A PEGylated analog of short-length Neuromedin U with potent anorectic and anti-obesity effects.
abstract: Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inooka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan. Electronic address: yasushi.masuda@takeda.com.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Terada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kumano
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yokoyama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Noguchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishizawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kamiguchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan. Electronic address: taiji.asami@takeda.com.
authors.forename: Taiji
authors.initials: T
authors.lastname: Asami
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Takekawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013552:Swine; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D009479:Neuropeptides; C056900:neuromedin U; D011092:Polyethylene Glycols
keywords: Diabetes; NMU-8; Neuromedin U (NMU); Obesity; Polyethylene glycol (PEG)