Designed Spiroketal Protein Modulation

Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐ba...

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Veröffentlicht in:	Angewandte Chemie International Edition Jg. 56; H. 20; S. 5480 - 5484
Hauptverfasser:	Scheepstra, Marcel, Andrei, Sebastian A., Unver, M. Yagiz, Hirsch, Anna K. H., Leysen, Seppe, Ottmann, Christian, Brunsveld, Luc, Milroy, Lech‐Gustav
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	WEINHEIM Wiley 08.05.2017 Wiley Subscription Services, Inc John Wiley and Sons Inc
Ausgabe:	International ed. in English
Schlagworte:	Allosteric properties Biological activity Chemistry Chemistry, Multidisciplinary Communication Communications Crystal structure Crystallography, X-Ray drug design Drug discovery Furans - chemistry Humans Lead compounds Models, Molecular Molecular Structure Natural products Nuclear Receptor Coactivator 2 - chemistry Physical Sciences Proteins Receptors Retinoid X Receptor alpha - chemistry Retinoid X receptors Science & Technology spiro compounds Spiro Compounds - chemistry structure elucidation THERAPEUTICS RUBROMYCIN RECOGNITION drug design NUCLEAR RECEPTORS NATURAL-PRODUCTS BIOLOGY-ORIENTED SYNTHESIS spiro compounds RXR natural products drug discovery structure elucidation RETINOID-X-RECEPTOR SCAFFOLDS SELECTIVITY
ISSN:	1433-7851, 1521-3773, 1521-3773
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Zusammenfassung:	Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes. Spiroketals for drug discovery: The structure‐based design, synthesis, and biochemical as well as structural validation of a spiroketal protein modulator are reported. The data suggests that the bisbenzannulated spiroketal functions as a potent partial agonist of the retinoid X receptor, thus highlighting the potential of spiroketals as de novo drug lead compounds.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.201612504