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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
Author(s) -
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
Publication year - 2014
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2582
Subject(s) - conjugate , chemistry , human serum albumin , medicine , endocrinology , peptide , in vivo , pharmacology , diabetes mellitus , biochemistry , biology , mathematical analysis , mathematics , microbiology and biotechnology
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. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.