The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts

Journal of Medicinal Chemistry
Zeljka KoradeNed A Porter

Abstract

Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to the screening of a small library of pharmacologically active substances, and the effect of compounds on the cholesterol pathway was determined. Of some 727 compounds, over 30 compounds decreased 7-DHC in Dhcr7-deficient Neuro2a cells. The examination of chemical structures of active molecules in the screen grouped the compounds into distinct categories. In addition to statins, our screen found that SERMs, antifungals, and several antipsychotic medications reduced levels of 7-DHC. The activities of selected compounds were verified in human fibroblasts derived from Smith-Lemli-Opitz syndrome (SLOS) patients and linked to specific transformations in the cholesterol biosynthesis pathway.

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Citations

Feb 28, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Josi HerronLibin Xu
Aug 12, 2016·Biomedical Chromatography : BMC·Tatsuya Higashi, Kazutake Shimada
Oct 4, 2017·Journal of Lipid Research·Zeljka KoradeNed A Porter
Jul 23, 2020·British Journal of Pharmacology·Philippe de MedinaMarc Poirot
Dec 21, 2018·JCI Insight·Elijah J WeberEdward J Kelly
Apr 9, 2019·Journal of Huntington's Disease·Anna C PfalzerAaron B Bowman
Jun 7, 2020·Molecular Psychiatry·Thiago C Genaro-MattosKároly Mirnics
Feb 3, 2021·ACS Chemical Neuroscience·Keri A TallmanZeljka Korade
Feb 3, 2021·Translational Psychiatry·Zeljka KoradeKaroly Mirnics
Dec 29, 2020·Frontiers in Genetics·Beatriz Carvalho HenriquesKatherine J Aitchison
Mar 9, 2021·ACS Omega·Thiago C Genaro-MattosKároly Mirnics
Feb 17, 2017·Schizophrenia Research·Željka KoradeChristine Konradi
Apr 7, 2021·Molecular Psychiatry·Zeljka KoradeKároly Mirnics
Apr 17, 2021·ACS Pharmacology & Translational Science·Thiago C Genaro-MattosKároly Mirnics
May 20, 2021·Biochemical Pharmacology·Babita MadanDavid J Leaver
Jun 28, 2019·ACS Chemical Neuroscience·Thiago C Genaro-MattosKároly Mirnics

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