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.

Abstract

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. 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 in vivo. 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.

• Authors: Philippe Neuner, Andrea M Peier, Fabio Talamo, Paolo Ingallinella, Armin Lahm, Gaetano Barbato, Annalise Di Marco, Kunal Desai, Karolina Zytko, Ying Qian, Xiaobing Du, Davide Ricci, Edith Monteagudo, Ralph Laufer, Alessandro Pocai, Elisabetta Bianchi, Donald J Marsh, Antonello Pessi
• Journal: Journal of peptide science : an official publication of the European Peptide Society (J Pept Sci) Vol. 20 Issue 1 Pg. 7-19 (Jan 2014) ISSN: 1099-1387 [Electronic] England
• PMID: 24222478 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

Chemical References

• Anti-Obesity Agents
• Blood Glucose
• HSA(IAc)-NMU
• Hypoglycemic Agents
• Neuropeptides
• PEG-NMU
• Receptors, Neurotransmitter
• Serum Albumin
• neuromedin U receptor
• Polyethylene Glycols
• Serum Albumin, Human

Topics

• Animals
• Anti-Obesity Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Blood Glucose
• Cell Line
• Drug Evaluation, Preclinical
• Humans
• Hypoglycemic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Neuropeptides (chemical synthesis, pharmacokinetics, pharmacology)
• Polyethylene Glycols (pharmacokinetics, pharmacology)
• Receptors, Neurotransmitter (agonists)
• Serum Albumin (chemical synthesis, pharmacokinetics, pharmacology)
• Serum Albumin, Human
• Weight Loss (drug effects)