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A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity

BACKGROUND: Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. PRINCIPAL FINDINGS: We synthesized no...

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Detalles Bibliográficos
Autores principales: Das, Bhaskar C., McCartin, Kellie, Liu, Ting-Chun, Peterson, Randall T., Evans, Todd
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848850/
https://www.ncbi.nlm.nih.gov/pubmed/20368991
http://dx.doi.org/10.1371/journal.pone.0010004
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author Das, Bhaskar C.
McCartin, Kellie
Liu, Ting-Chun
Peterson, Randall T.
Evans, Todd
author_facet Das, Bhaskar C.
McCartin, Kellie
Liu, Ting-Chun
Peterson, Randall T.
Evans, Todd
author_sort Das, Bhaskar C.
collection PubMed
description BACKGROUND: Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. PRINCIPAL FINDINGS: We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80–92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested. CONCLUSIONS: Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity.
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spelling pubmed-28488502010-04-05 A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity Das, Bhaskar C. McCartin, Kellie Liu, Ting-Chun Peterson, Randall T. Evans, Todd PLoS One Research Article BACKGROUND: Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model. PRINCIPAL FINDINGS: We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80–92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested. CONCLUSIONS: Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity. Public Library of Science 2010-04-02 /pmc/articles/PMC2848850/ /pubmed/20368991 http://dx.doi.org/10.1371/journal.pone.0010004 Text en Das et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Das, Bhaskar C.
McCartin, Kellie
Liu, Ting-Chun
Peterson, Randall T.
Evans, Todd
A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title_full A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title_fullStr A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title_full_unstemmed A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title_short A Forward Chemical Screen in Zebrafish Identifies a Retinoic Acid Derivative with Receptor Specificity
title_sort forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848850/
https://www.ncbi.nlm.nih.gov/pubmed/20368991
http://dx.doi.org/10.1371/journal.pone.0010004
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