Synthesis and evaluation of novel lipidated neuromedin U analogs with increased stability and effects on food intake. (17th December 2014)

• Record Type: Journal Article
• Authors: Dalbøge, Louise S.; Pedersen, Søren L.; van Witteloostuijn, Søren B.; Rasmussen, Jakob E.; Rigbolt, Kristoffer T. G.; Jensen, Knud J.; Holst, Birgitte; Vrang, Niels; Jelsing, Jacob
• Is Part Of: Journal of peptide science. Volume 21:Number 2(2015:Feb.)
• Page Start: 85
• Page End: 94
• Publication Date: 2014-12-17
• Subjects: Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.2727
• Languages: English
• ISSNs: 1075-2617

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Neuromedin U (NMU) is a 25 amino acid peptide expressed and secreted in the brain and gastrointestinal tract. Data have shown that peripheral administration of human NMU decreases food intake and body weight and improves glucose tolerance in mice, suggesting that NMU receptors constitute a possible anti‐diabetic and anti‐obesity drug target. However, the clinical use of native NMU is hampered by a poor pharmacokinetic profile. In the current study, we report <italic>in vitro</italic> and <italic>in vivo</italic> data from a series of novel lipidated NMU analogs.</p> <p> <italic>In vitro</italic> plasma stability studies of native NMU were performed to investigate the proteolytic stability and cleavage sites using LC–MS. Native NMU was found to be rapidly cleaved at the <italic>C</italic>‐terminus between Arg<sup>24</sup> and Asn<sup>25</sup>, followed by cleavage between Arg<sup>16</sup> and Gly<sup>17</sup>. Lipidated NMU analogs were generated using solid‐phase peptide synthesis, and <italic>in vitro</italic> potency was investigated using a human embryonic kidney 293‐based inositol phosphate accumulation assay. All lipidated analogs had preserved <italic>in vitro</italic> activity on both NMU receptors with potency improving as the lipidation site was moved away from the receptor‐interacting <italic>C</italic>‐terminal octapeptide segment.</p> <p> <italic>In vivo</italic> efficacy was assessed in lean mice as reduction in food intake after acute subcutaneous administration of 1, 0.3, 0.1, and 0.03 µmol/kg. These lipidated NMU analogs prolonged the anorectic effect of NMU in a dose‐dependent manner. This was likely an effect of improved pharmacokinetic properties because of improved vitro plasma stability. Accordingly, the data demonstrate that lipidated NMU analogs may represent drug candidates for the treatment of obesity. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.</p> </abstract>