Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein

Atherosclerosis related cardiovascular diseases continue to be the primary cause of mortality in developed countries. The elevated level of low density lipoprotein (LDL) is generally considered to be the driver of atherosclerosis, but recent years have seen a shift in this perception in that the vascular plaque buildup is mainly caused by oxidized LDL (ox-LDL) rather than native-LDL. The scavenger receptor LOX-1 found in endothelial cells binds and internalizes ox-LDL which leads to the initiation of plaque formation in arteries. Using virtual screening techniques, we identified a few potential small molecule inhibitors of LOX-1 and tested their inhibitory potential using differential scanning fluorimetry and various cellular assays. Two of these molecules significantly reduced the uptake of ox-LDL by human endothelial cells, LOX-1 transcription and the activation of ERK1/2 and p38 MAPKs in human endothelial cells. In addition, these molecules suppressed ox-LDL-induced VCAM-1 expression and monocyte adhesion onto human endothelial cells demonstrating their therapeutic potential.