The asialoglycoprotein receptor (ASGPR) is a C-type (Ca²⁺-dependent) lectin which is highly expressed on the surface of hepatocytes. The primary physiological role of ASGPR is considered to be binding, internalization, and subsequent clearance from the circulation of galactose- and N-acetylgalactosamine-terminated glycoproteins. The location and the function make the receptor an ideal target for delivery of therapeutic agents to liver cells.
Discovery of new ligands is an important goal in drug delivery. Quinoline derivatives has shown to be potent inhibitors of another C-type lectin (P-selectin)^1,2,3, marching to the clinical studies for the treatment of athero-thrombotic vascular events. Similar structures were obtained in the previously reported⁴ rational in silico screening for ASGPR ligands, albeit the measured affinity was relatively low. In this work we try to optimize the affinity of quinoline derivative structure. After in silico screening sixteen 3-hydroxyquinoline-4-carboxylic acid-derivatives were selected and synthesized. Due to the presence of hydroxyl at position 3, all structures had a solubility of at least 0.5 mM. The affinities to ASGPR has been assessed using surface plasmon resonance (SPR) spectroscopy technique. All structures exhibited strong binding affinity with K_D values in the nanomolar range (0.1 - 30 nM), that considerably exceed the affinities of native ASGPR ligands – N-acetylgalactosamine and galactose.
As all of the obtained compounds turned out to be potent ASGPR ligands one may consider quinoline-4-carboxylic acids to be a practically useful monovalent ligand as a cheaper, more available and more efficient GalNAc substituent as a vector for targeted drug delivery in hepatocytes.