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.

By Neuner, Philippe; Peier, Andrea M.; Talamo, Fabio; Ingallinella, Paolo; Lahm, Armin; Barbato, Gaetano; Di Marco, Annalise; Desai, Kunal; Zytko, Karolina; Qian, Ying; et al
From Journal of Peptide Science (2014), 20(1), 7-19. Language: English, Database: CAPLUS, DOI:10.1002/psc.2582

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 in vivo. The authors show here that conjugation of NMU to human serum albumin (HSA) yields a compd. 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 deriv. of the peptide with the free thiol of Cys 34 of HSA met with limited success, because the resulting conjugate was unstable in vivo. Use of a haloacetyl deriv. 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, the authors’ 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 & Sons, Ltd.