Development of potent and proteolytically stable human neuromedin U receptor agonists

TY - JOUR

T1 - Development of potent and proteolytically stable human neuromedin U receptor agonists

AU - De Prins, An

AU - Martin, Charlotte

AU - Van Wanseele, Yannick

AU - Skov, Louise Julie

AU - Tömböly, Csaba

AU - Tourwé, Dirk

AU - Caveliers, Vicky

AU - Van Eeckhaut, Ann

AU - Holst, Birgitte

AU - Rosenkilde, Mette Marie

AU - Smolders, Ilse

AU - Ballet, Steven

N1 - Copyright © 2017 Elsevier Masson SAS. All rights reserved.

PY - 2018/1/20

Y1 - 2018/1/20

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ejmech.2017.12.035

DO - 10.1016/j.ejmech.2017.12.035

M3 - Journal article

C2 - 29329072

SN - 0223-5234

VL - 144

SP - 887

EP - 897

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -