Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis

Tomar, Akanksha; Sahoo, Sibasis; Muthusankar, Aathi; Kuila, Shobhan; Khan, Mohd Azeem; Ravi, G.; Jeyaraman, Jeyakanthan; Mehta, J. L.; Varughese, Kottayil I.; Arockiasamy, A.

doi:10.1016/j.bbrc.2022.07.036

Cited by 5 publications

(7 citation statements)

References 27 publications

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“…Crucially, this independently identifies the Affimer binding site on LOX-1 as being the surface containing residues known to be involved in oxLDL association. This is the same surface also identified as containing the binding sites for small molecule inhibitors of LOX-1/oxLDL interaction ( 36 , 50 ).…”

Section: Discussionmentioning

confidence: 66%

“…Compounds recently described by Tomar et al. ( 50 ) had K D values measured by surface plasmon resonance in the range ∼5 to 2000 nM. Affimers achieve ≥90% inhibition of oxLDL binding at subnanomolar concentrations, with similar highly potent effects on signaling events triggered by receptor-ligand interaction.…”

Section: Discussionmentioning

confidence: 99%

“…These Affimers also showed subnanomolar potency either as inhibitors of oxLDL binding to LOX-1, or antagonists of oxLDL-mediated signaling through MAPK (ERK1/2). Given the ongoing debate around druggability of the LOX-1/oxLDL interaction ( 50 ), discovery of a completely novel set of potential inhibitors of this interaction opens up new avenues of investigation. Affimers could act as molecular probes to interrogate the interactions between receptor and ligand, or could themselves act as template biopharmaceuticals with beneficial effects on atherosclerotic plaque formation.…”

Section: Discussionmentioning

confidence: 99%

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“Affimer” synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation

Roper,

Tiede,

Abdul-Zani

et al. 2023

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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“Affimer” synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation

Roper,

Tiede,

Abdul-Zani

et al. 2023

Journal of Biological Chemistry

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“…Among the different oxLDL receptors, LOX-1 is a forerunner for targeted therapy because of its clear role in pathogenesis. Our computational analysis of crystal structure of LOX-1 CTLD dimer showed two key druggable sites: surface site and tunnel site [51 ▪ ]. Earlier studies showed that statins inhibit LOX-1-mediated oxLDL uptake and reduce the receptor expression in vitro [52,53].…”

Section: Targeting Oxldl Receptors For Future Therapymentioning

confidence: 84%

Oxidized LDL receptors: a recent update

Khan

Mohammad

Banerjee

et al. 2023

Current Opinion in Lipidology

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Purpose of review LDL in its oxidized form, or ‘oxLDL’, is now generally acknowledged to be highly proatherogenic and to play a significant role in atherosclerotic plaque formation. Therefore, there has been increasing interest in understanding the significance of oxLDL and its receptors in different phases of atherosclerosis, leading to the accumulation of additional data at the cellular, structural, and physiological levels. This review focuses on the most recent discoveries about these receptors and how they influence lipid absorption, metabolism, and inflammation in various cell types. Recent findings Two crystal structures of lectin-like oxLDL receptor-1 (LOX-1), one with a small molecule inhibitor and the other with a monoclonal antibody have been published. We recently demonstrated that the ‘surface site’ of LOX1, adjacent to the positively charged ‘basic spine region’ that facilitates oxLDL binding, is a targetable site for drug development. Further, recent human studies showed that soluble LOX-1 holds potential as a biomarker for cardiovascular disease diagnosis, prognosis, and assessing the efficacy of therapy. Summary Receptor-mediated oxLDL uptake results in cellular dysfunction of various cell types involved in atherogenesis and plaque development. The current advancements clearly demonstrate that targeting oxLDL-LOX-1 axis may lead to development of future therapeutics for the treatment of atherosclerotic cardiovascular and cerebrovascular diseases.

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“…Recently, Tomar et al . [47] have identified four molecules that can bind to two sites on LOX-1 potentially providing an avenue to explore novel inhibitors to dampen Ox-LDL and LOX-1 interaction.…”

Section: Novel Cardiovascular Risk Factors and Metabolic Syndromementioning

confidence: 99%

Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery

Bashir,

Adam,

et al. 2023

Current Opinion in Lipidology

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Purpose of review The aim of this study was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers. Recent findings Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality. Summary Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers.

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Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis

Cited by 5 publications

References 27 publications

“Affimer” synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation

“Affimer” synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation

Oxidized LDL receptors: a recent update

Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery

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