DIFFERENTIAL INTERACTIONS OF ANTIRETROVIRAL AGENTS WITH LXR, ER AND GR NUCLEAR RECEPTORS - POTENTIAL CONTRIBUTING FACTORS OF ADVERSE EVENTS
Citation:
J Svärd, F Blanco, D Nevin, D Fayne, F Mulcahy, M Hennessy and JP Spiers, DIFFERENTIAL INTERACTIONS OF ANTIRETROVIRAL AGENTS WITH LXR, ER AND GR NUCLEAR RECEPTORS - POTENTIAL CONTRIBUTING FACTORS OF ADVERSE EVENTS, British Journal of Pharmacology, 171, 2014, 480 - 497Download Item:
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Abstract:
BACKGROUND AND PURPOSE:
Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXRα/β), oestrogen receptors (ERα/β) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated.
EXPERIMENTAL APPROACH:
The ability of an ARV drug library to activate LXRα/β, ERα/β and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression.
KEY RESULTS:
Direct LBD interactions with LXRα and/or LXRβ were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/β in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir.
CONCLUSIONS AND IMPLICATIONS:
There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through 'off-target' effects involving nuclear receptor activation.
Author's Homepage:
http://people.tcd.ie/spiersjDescription:
PUBLISHED
Author: Spiers, James
Type of material:
Journal ArticleSeries/Report no:
British Journal of Pharmacology171
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Full text availableKeywords:
HIV protease inhibitorSubject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1111/bph.12480Licences: