Design and Synthesis of PEG-Oligoglycerol Sulfates as Multivalent Inhibitors for the Scavenger Receptor LOX-1.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a cell surface scavenger receptor. The protein is involved in binding and internalization of oxidized low-density lipoprotein (oxLDL), which leads under pathophysiological circumstances to plaque formation in arteries and initiation of atherosclerosis. A structural feature of LOX-1 relevant to oxLDL binding is the "basic spine" motif consisting of linearly aligned arginine residues stretched over the dimer surface. Inhibition of LOX-1 can be done by blocking these positively charged motifs. Here we report on the design, synthesis, and evaluation of a series of novel LOX-1 inhibitors having different numbers of sulfates and polyethylene glycerol (PEG) spacer. Two molecules, compounds 6b and 6d, showed binding affinity in the low nM range, i.e. 45.8 and 47.4 nM, respectively. The in vitro biological studies reveal that these molecules were also able to block the interaction of LOX-1 with its cognate ligands oxLDL, aged RBC, and bacteria.