Design of a novel LOX-1 receptor antagonist mimicking the natural substrate

Abstract

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is overexpressed in atherosclerotic lesions. LOX-1 specific inhibitors, urgently necessary to reduce the rate of atherosclerotic and inflammation processes, are not yet available. We have designed and synthesized a new modified oxidized phospholipid, named PLAzPC, which plays to small scale the ligand-receptor recognition scheme. Molecular docking simulations confirm that PLAzPC disables the hydrophobic component of the ox-LDL recognition domain and allows the interaction of the l-lysine backbone charged groups with the solvent and with the charged/polar residues located around the edges of the LOX-1 hydrophobic tunnel. Binding assays, in a cell model system expressing human LOX-1 receptors, confirm that PLAzPC markedly inhibits ox-LDL binding to LOX-1 with higher efficacy compared to previously identified inhibitors.

Keywords: 1,1′-dioctadecyl-3,3,3′,3′-tetramethyllindocarbocyanine perchlorate; 1-hydroxybenzotriazole; Atherosclerosis; C-type lectin-like domain; CTLD; Cell-based assay; DiI; HOBt; LDL; LOX-1; LOX-1 inhibitor; Molecular docking; Oxidized phospholipids; SRB; lectin-like oxidized low-density lipoprotein receptor-1; low-density lipoprotein; ox-LDL; oxidized low-density lipoprotein; sulforhodamine B.