Development of a neuromedin U–human serum albumin conjugate as a long‐acting candidate for the treatment of obesity and diabetes. Comparison with the PEGylated peptide. (13th November 2013)

• Record Type: Journal Article
• Authors: Neuner, Philippe; Peier, Andrea M.; Talamo, Fabio; Ingallinella, Paolo; Lahm, Armin; Barbato, Gaetano; Di Marco, Annalise; Desai, Kunal; Zytko, Karolina; Qian, Ying; Du, Xiaobing; Ricci, Davide; Monteagudo, Edith; Laufer, Ralph; Pocai, Alessandro; Bianchi, Elisabetta; Marsh, Donald J.; Pessi, Antonello
• Is Part Of: Journal of peptide science. Volume 20:Number 1(2014:Jan.)
• Page Start: 7
• Page End: 19
• Publication Date: 2013-11-13
• Subjects: Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.2582
• Languages: English
• ISSNs: 1075-2617

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Neuromedin U (NMU) is an endogenous peptide implicated in the regulation of feeding, energy homeostasis, and glycemic control, which is being considered for the therapy of obesity and diabetes. A key liability of NMU as a therapeutic is its very short half‐life <italic>in vivo</italic>. We show here that conjugation of NMU to human serum albumin (HSA) yields a compound with long circulatory half‐life, which maintains full potency at both the peripheral and central NMU receptors. Initial attempts to conjugate NMU via the prevalent strategy of reacting a maleimide derivative of the peptide with the free thiol of Cys34 of HSA met with limited success, because the resulting conjugate was unstable <italic>in vivo</italic>. Use of a haloacetyl derivative of the peptide led instead to the formation of a metabolically stable conjugate. HSA–NMU displayed long‐lasting, potent anorectic, and glucose‐normalizing activity. When compared side by side with a previously described PEG conjugate, HSA–NMU proved superior on a molar basis. Collectively, our results reinforce the notion that NMU‐based therapeutics are promising candidates for the treatment of obesity and diabetes. Copyright © 2013 European Peptide Society and John Wiley &amp; Sons, Ltd.</p> </abstract>