PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes
PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes
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DOI：
10.1016/j.bmc.2012.06.003
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Pessi, Antonello
中科院分区：
文献类型：
--
作者：
Ingallinella, Paolo;Peier, Andrea M.;Pessi, Antonello
Neuromedin U(NMU)是一种内源性多肽，其在调节摄食和能量平衡方面的作用已得到充分证实。已经确定了两种NMU受体：NMUR1，主要在外周表达，以及NMUR2，主要在大脑中表达。我们最近证明，NMU的急性外周给药具有强烈的急性厌食活性，并可以改善血糖稳态，这两种作用都由NMUR1介导。在这里，我们描述了一种代谢稳定的NMU类似物的开发，基于天然多肽与高分子量聚乙二醇衍生物(聚乙二醇化)(聚乙二醇化)。优化了聚乙二醇组分的大小、连接位置和连接化学，以产生一种在体内表现出强大和持久的厌食活性和显著的降糖活性的类似物。对NMU受体缺陷小鼠的研究表明，PEG-NMU显示出扩展的药理学特征，除了NMUR1之外，还具有参与NMUR2的能力。根据这些数据，NMU的聚乙二醇化衍生物是治疗肥胖症和糖尿病的有前途的候选药物。(C)2012爱思唯尔有限公司。保留所有权利。
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. (C) 2012 Elsevier Ltd. All rights reserved.