Development of potent and proteolytically stable human neuromedin U receptor agonists

An De Prins, Charlotte Martin, Yannick Van Wanseele, Louise Julie Skov, Csaba Tömböly, Dirk Tourwe, Vicky Caveliers, Ann Van Eeckhaut, Birgitte Holst, Mette Marie Rosenkilde, Ilse Smolders, Steven Ballet

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)887-897
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume144
DOIs
Publication statusPublished - 20 Jan 2018

Keywords

  • Neuromedin U (NMU)
  • Neuromedin U receptor agonists
  • NMU-8
  • Plasma stability

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