title: 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.
authors.affiliation: Department of Biology, Interuniversity Consortium, National Institute Biostructure and Biosystem (INBB), University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy. falconi@uniroma2.it
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.forename: Sarah
authors.initials: S
authors.lastname: Ciccone
authors.forename: Paola
authors.initials: P
authors.lastname: D'Arrigo
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Viani
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorge
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Patrizi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
authors.forename: Silvia
authors.initials: S
authors.lastname: Biocca
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D062105:Molecular Docking Simulation; D010100:Oxygen / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D010743:Phospholipids; D051127:Scavenger Receptors, Class E; D004247:DNA; D008239:Lysine; D010100:Oxygen
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