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

2017 Fiscal Year Final Research Report

• 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
• 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.

Free Research Field

創薬化学