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A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state
Communications Chemistry ( IF 5.9 ) Pub Date : 2020-06-10 , DOI: 10.1038/s42004-020-0321-2
Gisela Schnapp 1 , Heike Neubauer 1 , Frank H Büttner 1 , Sandra Handschuh 1 , Iain Lingard 1, 2 , Ralf Heilker 1 , Klaus Klinder 1 , Jürgen Prestle 1 , Rainer Walter 1 , Michael Wolff 1 , Markus Zeeb 1 , Francois Debaene 3 , Herbert Nar 1 , Dennis Fiegen 1
Affiliation  

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.



中文翻译:

凝集素样氧化 LDL 受体 1 的小分子抑制剂通过稳定无活性受体四聚体状态起作用

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。

更新日期:2020-06-10
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