Ligand–Phospholipid Conjugation: A Versatile Strategy for Developing Long-Acting Ligands That Bind to Membrane Proteins by Restricting the Subcellular Localization of the Ligand

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.