Development of potent and proteolytically stable human neuromedin U receptor agonists.

Charlotte Martin
Charlotte Martin
University of Newcastle
Louise Julie Skov
Louise Julie Skov
Laboratory for Molecular Pharmacology
Dirk Tourwe
Dirk Tourwe
Vrije Universiteit Brussel
Vicky Caveliers
Vicky Caveliers
In Vivo Cellular and Molecular Imaging Laboratory

Eur J Med Chem 2018 Jan 14;144:887-897. Epub 2017 Dec 14.

Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium. Electronic address:

Neuromedin U (NMU) is a highly conserved endogenous peptide that is involved in a wide range of physiological processes such as regulation of feeding behavior, the stress response and nociception. The major limitation to use NMU as a therapeutic is its short half-life. Here, we describe the development of a set of novel NMU-analogs based on NMU-8, by introducing unnatural amino acids into the native sequence. This approach shows that it is possible to generate molecules with increased potency and improved plasma stability without major changes of the peptidic nature or the introduction of large conjugates. When compared to the native NMU-8 peptide, compounds 16, 18 and 20 have potent agonist activity and affinity for both NMU receptors. Selectivity towards NMUR1 was observed when the Phe residue in position 4 was modified, whereas higher potencies at NMUR2 were found when substitutions of the Pro residue in position 6 were executed. To study the effect of the modifications on the proteolytic stability of the molecules, an in vitro stability assay in human plasma at 37 °C was performed. All analyzed analogs possessed an increased resistance against enzymatic degradation in human plasma resulting in half-lifes from 4 min for NMU-8, up to more than 23 h for compound 42.
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January 2018
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