By Harper, Steven; McCauley, John A.; Rudd, Michael T.; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta;…
By Ingallinella, Paolo; Peier, Andrea M.; Pocai, Alessandro; Di Marco, Annalise; Desai, Kunal; Zytko, Karolina; Qian, Ying; Du, Xiaobing; Cellucci, Antonella; Monteagudo, Edith; et al
From Bioorganic & Medicinal Chemistry (2012), 20(15), 4751-4759. Language: English, Database: CAPLUS, DOI:10.1016/j.bmc.2012.06.003
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 mol. wt. poly(ethylene) glycol (PEG) (‘PEGylation’). PEG size, site of attachment, and conjugation chem. 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 pharmacol. profile, with the ability to engage NMUR2 in addn. to NMUR1. In light of these data, PEGylated derivs. of NMU represent promising candidates for the treatment of obesity and diabetes.