A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity
| Autor: | Randall T. Peterson, Ting-Chun Liu, Kellie McCartin, Todd Evans, Bhaskar C. Das |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Embryo
Nonmammalian Receptors Retinoic Acid medicine.drug_class Drug Evaluation Preclinical Retinoic acid lcsh:Medicine Antineoplastic Agents Tretinoin Biology Pharmacology Retinoid X receptor 01 natural sciences Small Molecule Libraries Retinoids Developmental Biology/Molecular Development 03 medical and health sciences chemistry.chemical_compound Chemical Biology medicine Animals Retinoid lcsh:Science Zebrafish Developmental Biology/Embryology 030304 developmental biology 0303 health sciences Multidisciplinary Retinoid X receptor alpha Developmental Biology/Morphogenesis and Cell Biology 010405 organic chemistry lcsh:R biology.organism_classification Retinoid X receptor gamma 0104 chemical sciences Cell biology chemistry Chemical Biology/Biomimetic Chemistry lcsh:Q Retinoid X receptor beta Protein Binding Research Article Developmental Biology medicine.drug |
| Zdroj: | PLoS ONE, Vol 5, Iss 4, p e10004 (2010) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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