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.
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.
IRBM P. Angeletti, 00040, Pomezia, RM, Italy; NIBR WSJ-507.1.02, Novartis Pharma AG, Campus, CH-4056, Basel, Switzerland.
Philippe
P
Neuner
Andrea M
AM
Peier
Fabio
F
Talamo
Paolo
P
Ingallinella
Armin
A
Lahm
Gaetano
G
Barbato
Annalise
A
Di Marco
Kunal
K
Desai
Karolina
K
Zytko
Ying
Y
Qian
Xiaobing
X
Du
Davide
D
Ricci
Edith
E
Monteagudo
Ralph
R
Laufer
Alessandro
A
Pocai
Elisabetta
E
Bianchi
Donald J
DJ
Marsh
Antonello
A
Pessi
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000819:agonists; D012709:Serum Albumin / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000075462:Serum Albumin, Human; D015431:Weight Loss / Q000187:drug effects
D019440:Anti-Obesity Agents; D001786:Blood Glucose; C000590531:HSA(IAc)-NMU; D007004:Hypoglycemic Agents; D009479:Neuropeptides; C000590532:PEG-NMU; D017981:Receptors, Neurotransmitter; D012709:Serum Albumin; C082444:neuromedin U receptor; D011092:Polyethylene Glycols; D000075462:Serum Albumin, Human
conjugate; diabetes; human serum albumin; neuromedin U; obesity