PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes

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• 作者：Paolo Ingallinella ; Andrea M. Peier ; Aless ; ro Pocai ; Annalise Di Marco ; Kunal Desai ; Karolina Zytko ; Ying Qian ; Xiaobing Du ; Antonella Cellucci ; Edith Monteagudo ; Ralph Laufer ; Elisabetta Bianchi ; Donald J. Marsh ; Antonello Pessi
• 关键词：Neuromedin U ; Diabetes ; Obesity ; PEG
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：20
• 期：15
• 页码：4751-4759
• 全文大小：383 K

文摘

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.