Gisela Schnapp, Heike Neubauer, Frank H Büttner, Sandra Handschuh, Iain Lingard, Ralf Heilker, Klaus Klinder, Jürgen Prestle, Rainer Walter, Michael Wolff, Markus Zeeb, François Debaene*, Herbert Nar, Dennis Fiegen
Schnapp, G., Neubauer, H., Büttner, F.H. et al. Commun Chem 3, 75 (2020). https://doi.org/10.1038/s42004-020-0321-2
Abstract:
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.
* author from NovAliX