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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Bibliographic Details
Published in:Angewandte Chemie International Edition Vol. 56; no. 20; pp. 5480 - 5484
Main Authors: Scheepstra, Marcel, Andrei, Sebastian A., Unver, M. Yagiz, Hirsch, Anna K. H., Leysen, Seppe, Ottmann, Christian, Brunsveld, Luc, Milroy, Lech‐Gustav
Format: Journal Article
Language:English
Published: WEINHEIM Wiley 08.05.2017
Wiley Subscription Services, Inc
John Wiley and Sons Inc
Edition:International ed. in English
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.201612504