title: PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes.
abstract: Neuromedin U (NMU) is an endogenous peptide, whose role in the regulation of feeding and energy homeostasis is well documented. Two NMU receptors have been identified: NMUR1, expressed primarily in the periphery, and NMUR2, expressed predominantly in the brain. We recently demonstrated that acute peripheral administration of NMU exerts potent but acute anorectic activity and can improve glucose homeostasis, with both actions mediated by NMUR1. Here, we describe the development of a metabolically stable analog of NMU, based on derivatization of the native peptide with high molecular weight poly(ethylene) glycol (PEG) ('PEGylation'). PEG size, site of attachment, and conjugation chemistry were optimized, to yield an analog which displays robust and long-lasting anorectic activity and significant glucose-lowering activity in vivo. Studies in NMU receptor-deficient mice showed that PEG-NMU displays an expanded pharmacological profile, with the ability to engage NMUR2 in addition to NMUR1. In light of these data, PEGylated derivatives of NMU represent promising candidates for the treatment of obesity and diabetes.
authors: IRBM P. Angeletti, 00040 Pomezia (RM), Italy.
authors: Paolo
authors: P
authors: Ingallinella
authors: Andrea M
authors: AM
authors: Peier
authors: Alessandro
authors: A
authors: Pocai
authors: Annalise Di
authors: AD
authors: Marco
authors: Kunal
authors: K
authors: Desai
authors: Karolina
authors: K
authors: Zytko
authors: Ying
authors: Y
authors: Qian
authors: Xiaobing
authors: X
authors: Du
authors: Antonella
authors: A
authors: Cellucci
authors: Edith
authors: E
authors: Monteagudo
authors: Ralph
authors: R
authors: Laufer
authors: Elisabetta
authors: E
authors: Bianchi
authors: Donald J
authors: DJ
authors: Marsh
authors: Antonello
authors: A
authors: Pessi
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D009765:Obesity / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000819:agonists* / Q000172:deficiency; D013329:Structure-Activity Relationship
chemical_list: D009479:Neuropeptides; C000590532:PEG-NMU; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; D011092:Polyethylene Glycols