A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state

Gisela Schnapp,Frank H Büttner,Francois Debaene,Michael Wolff,Markus Zeeb,Heike Neubauer,Sandra Handschuh,Ralf Heilker,Klaus Klinder,Herbert Nar,Iain Lingard,Dennis Fiegen,Jürgen Prestle,Rainer Walter

doi:10.1038/s42004-020-0321-2

Gisela Schnapp, Frank H Büttner + Show 12 more

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https://doi.org/10.1038/s42004-020-0321-2

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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.

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The C-type lectin family member lectin-like oxidized LDL receptor-1 (LOX-1) has been object of intensive research
Besides the major risk factors such as high serum levels of total cholesterol or low-density lipoprotein cholesterol (LDLC), non-traditional risk factors are emerging as being important for predisposing to this disease, as many coronary artery disease (CAD) events are not prevented by only LDLC lowering therapy
To identify small molecule inhibitors of LOX-1 mediated oxidized low-density lipoproteins (oxLDL) uptake we developed a cellular high throughput screening (HTS) assay

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The C-type lectin family member lectin-like oxidized LDL receptor-1 (LOX-1) has been object of intensive research. We provide the crystallographic structure of a small molecule (BI-0115)-LOX-1 receptor complex, which shows atomic details of the protein-ligand interaction and the structural basis of the inhibitory mode-of-action. To identify small molecule inhibitors of LOX-1 mediated oxLDL uptake we developed a cellular high throughput screening (HTS) assay.

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