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Issue 8, 2019
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Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool

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Abstract

Guggulsterone is a promiscuous ligand for endocrine and metabolic lipid receptors traditionally used to treat a number of diseases including diabesity, hyperlipidemia, atherosclerosis, and osteoarthritis. Although relatively weak, its activity at the farnesoid X receptor (FXR) is particularly intriguing as guggulsterone acts as an antagonist with a peculiar ability of gene selective modulation. We report here a chemical biology study with the aim to further characterize the biological action of guggulsterone at the FXR and to obtain further insights into the functional role played by noncanonical FXR binding pockets S2 and S3. Our results suggest that the FXR accessory pockets might act as potential targets for small molecules able to modulate the metabolic activation of the receptor without affecting the anti-inflammatory activity thus revealing a new approach for disclosing selective FXR modulators that might bypass potential side-effects from chronic treatments.

Graphical abstract: Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool

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Article information


Submitted
08 May 2019
Accepted
16 Jun 2019
First published
24 Jun 2019

Med. Chem. Commun., 2019,10, 1412-1419
Article type
Research Article

Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool

D. Passeri, A. Carotti, J. M. R. Pittol, G. Ciaccioli, R. Pellicciari, S. W. C. van Mil and A. Gioiello, Med. Chem. Commun., 2019, 10, 1412
DOI: 10.1039/C9MD00264B

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