Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.

Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives

“…For example, the synthetic FXR agonist Px‐102/Px‐104 (and the follow‐up compound GS‐9674) is being tested in a phase IIa randomized, clinical trial in patients with NAFLD (http://www.clinicaltrials.gov identifier: NCT01999101), and the selective and highly potent WAY‐362450/FXR‐450 compound is in early‐phase clinical development (ClinicalTrials.gov identifier: NCT00499629). Indeed, this is a very active area, and other agents that will likely emerge as novel FXR modulators continue to be developed . A recent mouse study using an intestinal‐restricted FXR agonist, fexaramine, also raises questions regarding the optimal target tissue for FXR agonism to treat metabolic disease .…”

Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin

“…The analyses of the transcriptional activity of FXR mutants revealed several important residues for IVM binding (Jin et al . , ) (Fig. B ).…”

“…) and FXR (Jin et al . ). IVM is the most potent among the analogues to activate GluCl; ABM possesses a similar efficacy to IVM in the activation of GlyR, the P2X 4 receptor, GIRK channels and FXR; DOM shows a lesser activation or potentiation effect on the P2X 4 receptor and GIRK channels than IVM; EPM does not modulate FXR‐mediated signalling.…”

“…) and the regulation of metabolism by modulation of FXR signalling (Jin et al . ). In the case of the invertebrate GluCl, IVM is most potent and ABM and others are less effective (Arena et al .…”

“…For example, EPM did not rescue the metabolic syndrome by targeting FXR (Jin et al . ). These results suggest that the structural difference in disaccharide moiety also influences its binding.…”