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LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring
Published on: November 17, 2018
A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer
Gisela Schnapp1, Heike Neubauer1, Frank H Büttner1
1Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach, Germany.
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.
Insights
Researchers identified BI-0115, a novel small molecule inhibitor of lectin-like oxidized LDL receptor-1 (LOX-1). This compound selectively blocks oxidized LDL uptake, offering potential therapeutic strategies for cardiovascular diseases and cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Lectin-like oxidized LDL receptor-1 (LOX-1) is a C-type lectin receptor involved in vascular cell uptake of oxidized LDL (oxLDL).
- LOX-1 plays a critical role in endothelial dysfunction, atherosclerosis progression, and has potential therapeutic implications in cardiovascular diseases and cancer.
- Few selective compounds targeting the oxLDL-LOX-1 interaction have been characterized.
Purpose of the Study:
- To identify and characterize a novel small molecule inhibitor of LOX-1.
- To investigate the mechanism by which the inhibitor blocks oxLDL binding to LOX-1.
- To explore the therapeutic potential of LOX-1 inhibition.
Main Methods:
- High-throughput screening to identify potential inhibitors.
- Biophysical analysis to characterize inhibitor binding and mechanism of action.
- Structural studies of LOX-1 in complex with the inhibitor.
Main Results:
- BI-0115 was identified as a selective small molecule inhibitor of LOX-1.
- BI-0115 blocks the cellular uptake of oxLDL.
- Biophysical and structural analyses revealed that BI-0115 binding induces LOX-1 dimerization and subsequent tetramer formation, inhibiting oxLDL binding.
Conclusions:
- BI-0115 is a potent and selective LOX-1 inhibitor.
- The mechanism of inhibition involves the formation of a LOX-1 tetramer mediated by BI-0115.
- BI-0115 represents a promising therapeutic lead for conditions associated with LOX-1 activity, such as atherosclerosis.
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