The C-type lectin family member lectin-like oxidized LDL receptor-1 (LOX-1) has been object of intensive research. Its modulation may offer a broad spectrum of therapeutic interventions ranging from cardiovascular diseases to cancer. LOX-1 mediates uptake of oxLDL by vascular cells and plays an important role in the initiation of endothelial dysfunction and its progression to atherosclerosis. So far only a few compounds targeting oxLDL-LOX-1 interaction are reported with a limited level of characterization. Here we describe the identification and characterization of BI-0115, a selective small molecule inhibitor of LOX-1 that blocks cellular uptake of oxLDL. Identified by a high throughput screening campaign, biophysical analysis shows that BI-0115 binding triggers receptor inhibition by formation of dimers of the homodimeric ligand binding domain. The structure of LOX-1 bound to BI-0115 shows that inter-ligand interactions at the receptor interfaces are key to the formation of the receptor tetramer thereby blocking oxLDL binding.

C型凝集素家族成员凝集素样氧化低密度脂蛋白受体-1（LOX-1）一直是深入研究的对象。它的调制可能提供从心血管疾病到癌症的广泛治疗干预。LOX-1 介导血管细胞摄取 oxLDL，在内皮功能障碍的启动及其向动脉粥样硬化的进展中起重要作用。到目前为止，只有少数靶向 oxLDL-LOX-1 相互作用的化合物被报道，其表征水平有限。在这里，我们描述了 BI-0115 的鉴定和表征，BI-0115 是一种选择性的 LOX-1 小分子抑制剂，可阻止细胞摄取 oxLDL。通过高通量筛选活动鉴定，生物物理分析表明，BI-0115 结合通过形成同型二聚体配体结合域的二聚体来触发受体抑制。