2. Academic Validation
  3. 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.
PMID: 32247748 DOI: 10.1016/j.bmc.2020.115454
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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