A Versatile Strategy for Developing Long-Acting Ligands by Ligand-Phospholipid Conjugation

• Project/Area Number: 16K15136
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Hokkaido University
• Principal Investigator: SHUTO Satoshi 北海道大学, 薬学研究院, 教授 (70241346)
• Co-Investigator(Kenkyū-buntansha): 福田 隼 長崎大学, 医歯薬学総合研究科(薬学系), 准教授 (30434450)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: レジデンスタイム / リン脂質 / トルテロジン / ムスカリン受容体

Outline of Final Research Achievements

We hypothesized that if drug localization can be restricted to a particular subcellular domain where their target proteins reside, the drugs could bind to their target proteins without being metabolized and/or excreted, which would significantly extend the half-life of the corresponding drug-target complex. Thus, we designed ligand-phospholipid conjugates, in which the ligand is conjugated with a phospholipid through a polyethylene glycol linker, to restrict the subcellular localization of the ligand in the vicinity of the lipid bilayer. Here, we present the design, synthesis, pharmacological activity, and binding mode analysis of ligand-phospholipid conjugates with muscarinic acetylcholine receptors as the target proteins. These results demonstrate that ligand-phospholipid conjugation can be a versatile strategy for developing long-acting ligands that bind to membrane proteins in drug discovery.

Research Products

• [Journal Article] Ligand-Phospholipid Conjugation: a Versatile Strategy for Developing Long-Acting Ligands that Bind to Membrane Proteins by Restricting the Subcellular Localization of the Ligand (2018)
  • Author(s): S. Kawamura, Y. Ito, T. Hirokawa, E. Hikiyama, S. Yamada, S. Shuto
  • Journal Title: J. Med. Chem Volume: 未定
  • Peer Reviewed
• [Journal Article] Novel Characteristics of Guanosine 5’-monophosphate 1 Reductase in Pathogenic2 Protozoa Trypanosoma brucei Distinct from Host Animal. (2016)
  • Author(s): T. Bessho, T. Okada, C. Kimura, T. Shinohara, A. Tomiyama, A. Imamura, M. Kuwamura, K. Nishimura, K. Fujimori, .S. Shuto, O. Ishibashi, B. K. Kubata, T. Inui
  • Journal Title: PLoS Negl. Trop. Dis Volume: 10 Issue: 1 Pages: e0004339-e0004339
  • DOI: 10.1371/journal.pntd.0004339
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction (2016)
  • Author(s): Hayato Fukuda, Saki Ito, Kenji Watari, Chihiro Mogi, Mitsuhiro Arisawa, Fumikazu Okajima, Hitoshi Kurose, Satoshi Shuto
  • Journal Title: ACS Med. Chem. Lett. Volume: 7 Issue: 5 Pages: 493-497
  • DOI: 10.1021/acsmedchemlett.6b00014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout. (2016)
  • Author(s): K. Tatani, M. Hiratochi, N. Kikuchi, Y. Kuramochi, S. Watanabe, Y. Yamauchi, M. Isaji, S, Shuto
  • Journal Title: J. Med. Chem Volume: 59 Issue: 8 Pages: 3719-3731
  • DOI: 10.1021/acs.jmedchem.5b01884
  • Peer Reviewed
• [Journal Article] Highly Sensitive Measurement of Inositol 1,4,5-Trisphosphate by Using a New Fluorescent Ligand and Ligand Binding Domain Combination (2016)
  • Author(s): Oura, T.; Murata, K.; Morita, T.; Nezu, A.; Arisawa, M.; Shuto, S.; Tanimura, A.
  • Journal Title: ChemBioChem Volume: 17 Issue: 16 Pages: 1509-1512
  • DOI: 10.1002/cbic.201600096
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Design, Synthesis, and Identification of 4α-azidoethyl-Cyclic ADP-Carbocyclic-Ribose as a Highly Potent Analogue of Cyclic ADP-Ribose a Ca2+-mobilizing Second Messenger (2016)
  • Author(s): Sato, T.; Watanabe, M.; Tsuzuki, T.; Takano, S.; Murayama, T.; Sakurai, T.; Kameda, T.; Arisawa, M.; Fukuda, H.; Shuto, S.
  • Journal Title: J. Med. Chem. Volume: 59 Issue: 15 Pages: 7282-7286
  • DOI: 10.1021/acs.jmedchem.6b00437
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of a Sulfur-Modified Glass-Supported Pd Nanoparticle Catalyst for Suzuki–Miyaura Coupling (2016)
  • Author(s): Mincen Xiao, Naoyuki Hoshiya, Katsumasa Fujiki, Tetsuo Honma, Yusuke Tamenori, Satoshi Shuto, Hiromichi Fujioka, Mitsuhiro Arisawa
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 8 Pages: 1154-1160
  • DOI: 10.1248/cpb.c16-00261
  • NAID: 130005253911
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Design and Synthesis of Cyclopropane Congeners of Resolvin E2, an Endogenous Proresolving Lipid Mediator, as Its Stable Equivalents (2016)
  • Author(s): Fukuda, H; Muromoto, R.; Takakura, Y.; Ishimura, K.; Kanada, R.; Fushihara, D.; Tanabe, M.; Matsubara, K.; Hirao, T.; Hirashima, K.; Abe, Arisawa, M.; Matsuda, T.; Shuto, S.
  • Journal Title: Org. Lett. Volume: 18 Issue: 24 Pages: 6224-6227
  • DOI: 10.1021/acs.orglett.6b02612
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant