Daniel Zaienne, Laura Isigkeit, Dr. Julian A. Marschner, Silke Duensing-Kropp, Dr. Georg Höfner, Prof. Dr. Daniel Merk
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引用次数: 1
摘要
类视黄醇X受体(Retinoid X receptor, RXR)是一种配体感应转录因子，作为普遍的异二聚体伴侣，在核受体信号传导中具有独特的作用。RXR调节在癌症、神经退行性疾病和代谢性疾病中具有潜力，但RXR激活的不利影响和缺乏选择性调节剂阻碍了其作为治疗靶点的进一步探索。天然产物戊酸已被发现为RXR激动剂，具有前所未有的RXR亚型和同型二聚体激活偏好。为了捕获这种活性分布的结构决定因素并确定优化的潜力，我们研究了天然产物的结构修饰对RXR调节的影响，并确定了具有增强RXR同型二聚体激动作用的类似物。
Structural Modification of the Natural Product Valerenic Acid Tunes RXR Homodimer Agonism
Retinoid X receptors (RXR) are ligand-sensing transcription factors with a unique role in nuclear receptor signaling as universal heterodimer partners. RXR modulation holds potential in cancer, neurodegeneration and metabolic diseases but adverse effects of RXR activation and lack of selective modulators prevent further exploration as therapeutic target. The natural product valerenic acid has been discovered as RXR agonist with unprecedented preference for RXR subtype and homodimer activation. To capture structural determinants of this activity profile and identify potential for optimization, we have studied effects of structural modification of the natural product on RXR modulation and identified an analogue with enhanced RXR homodimer agonism.
期刊介绍：
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
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