1. Academic Validation
  2. A chemically stable peptide agonist to neuromedin U receptor type 2

A chemically stable peptide agonist to neuromedin U receptor type 2

  • Bioorg Med Chem. 2020 May 15;28(10):115454. doi: 10.1016/j.bmc.2020.115454.
Kentaro Takayama 1 Kenji Mori 2 Akiko Tanaka 3 Yu Sasaki 4 Yuko Sohma 4 Akihiro Taguchi 4 Atsuhiko Taniguchi 4 Toshiyasu Sakane 3 Akira Yamamoto 5 Mikiya Miyazato 2 Naoto Minamino 6 Kenji Kangawa 2 Yoshio Hayashi 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan; Department of Environmental Biochemistry, Kyoto Pharmaceutical University, 5 Misasaginakauchi-cho, Yamashina, Kyoto 607-8414, Japan. Electronic address: ktaka59@mb.kyoto-phu.ac.jp.
  • 2 Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.
  • 3 Laboratory of Pharmaceutical Technology, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe, Hyogo 658-8558, Japan.
  • 4 Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
  • 5 Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Misasaginakauchi-cho, Yamashina, Kyoto 607-8414, Japan.
  • 6 Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.
  • 7 Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan. Electronic address: yhayashi@toyaku.ac.jp.
Abstract

Neuromedin U (NMU) is a peptide with appetite suppressive activity and other physiological activities via activation of the NMU receptors NMUR1 and NMUR2. In 2014, we reported the first NMUR2 selective agonist, 3-cyclohexylpropionyl-Leu-Leu-Dap-Pro-Arg-Asn-NH2 (CPN-116). However, we found that CPN-116 in phosphate buffer is unstable because of Nα-to-Nβ acyl migration at the Dap residue. In this study, the chemical stability of CPN-116 was evaluated under various conditions, and it was found to be relatively stable in buffers such as HEPES and MES. We also performed a structure-activity relationship study to obtain an NMUR2-selective agonist with improved chemical stability. Consequently, CPN-219 bearing a Dab residue in place of Dap emerged as a next-generation hexapeptidic NMUR2 agonist.

Keywords

Agonist; Chemical stability; Good’s buffer; Neuromedin U receptor type 2; Peptide.

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