TY - JOUR
T1 - The Effect of Small Molecules on Sterol Homeostasis
T2 - Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts
AU - Korade, Zeljka
AU - Kim, Hye Young H.
AU - Tallman, Keri A.
AU - Liu, Wei
AU - Koczok, Katalin
AU - Balogh, Istvan
AU - Xu, Libin
AU - Mirnics, Karoly
AU - Porter, Ned A.
N1 - Funding Information:
We thank Dr. H. Ronald Zielke and UMB Brain and Tissue Bank/NIH NeuroBioBank for donation of UMB727 (http://medschool.umaryland.edu/btbank/). The National Institutes of Health (NICHD R01 HD064727 to N.A.P., NIEHS R01 ES024133 to N.A.P. and Z.K., R21 ES024666 to N.A.P.) and the Hungarian Research Fund OTKA K109076 to I.B. supported this work. Assay development and preparation was carried out with assistance from Paige Vinson and Joshua Bauer in the Vanderbilt High-throughput Screening Core Facility, which receives institutional support through the Vanderbilt Institute of Chemical Biology. The NIH Clinical Collection is provided through the National Institutes of Health Molecular Libraries Roadmap Initiative.
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/2/11
Y1 - 2016/2/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958213961&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958213961&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b01696
DO - 10.1021/acs.jmedchem.5b01696
M3 - Article
C2 - 26789657
AN - SCOPUS:84958213961
SN - 0022-2623
VL - 59
SP - 1102
EP - 1115
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -