Planta Med 2020; 86(15): 1097-1107
DOI: 10.1055/a-1171-8357
Biological and Pharmacological Activity
Original Papers

Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport[ # ]

Angela Ladurner
1  Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Thomas Linder
2  Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria
,
Limei Wang
1  Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Verena Hiebl
1  Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Daniela Schuster
3  Department of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
4  Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University, Salzburg, Austria
,
Michael Schnürch
2  Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria
,
Marko D. Mihovilovic
2  Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria
,
Atanas G. Atanasov
1  Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
5  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, Poland
6  Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
7  Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Vienna, Austria
,
Verena M. Dirsch
1  Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
› Author Affiliations
Supported by: Hochschuljubiläumsstiftung der Stadt Wien H-268438/2018
Supported by: Austrian Science Fund S10704
Supported by: Austrian Science Fund S10710
Supported by: Austrian Science Fund S10711

Abstract

The ligand-activated farnesoid X receptor is an emerging therapeutic target for the development of drugs against metabolic syndrome-related diseases. In this context, selective bile acid receptor modulators represent a novel concept for drug development. Selective bile acid receptor modulators act in a target gene- or tissue-specific way and are therefore considered less likely to elicit unwanted side effects. Based on leoligin, a lignan-type secondary plant metabolite from the alpine plant Leontopodium nivale ssp. alpinum, 168 synthesized structural analogs were screened in a farnesoid X receptor in silico pharmacophore-model. Fifty-six virtual hits were generated. These hits were tested in a cell-based farnesoid X receptor transactivation assay and yielded 7 farnesoid X receptor-activating compounds. The most active one being LT-141A, with an EC50 of 6 µM and an Emax of 4.1-fold. This analog did not activate the G protein-coupled bile acid receptor, TGR5, and the metabolic nuclear receptors retinoid X receptor α, liver X receptors α/β, and peroxisome proliferator-activated receptors β/γ. Investigation of different farnesoid X receptor target genes characterized LT-141A as selective bile acid receptor modulators. Functional studies revealed that LT-141A increased cholesterol efflux from THP-1-derived macrophages via enhanced ATP-binding cassette transporter 1 expression. Moreover, cholesterol uptake in differentiated Caco-2 cells was significantly decreased upon LT-141A treatment. In conclusion, the leoligin analog LT-141A selectively activates the nuclear receptor farnesoid X receptor and has an influence on cholesterol transport in 2 model systems.

# Dedicated to Professor Dr. Wolfgang Kubelka on the occasion of his 85th birthday.


Supporting Information



Publication History

Received: 14 January 2020

Accepted: 05 May 2020

Publication Date:
02 June 2020 (online)

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