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Designed Spiroketal Protein Modulation

Scheepstra, M., Andrei, S. A., Unver, M. Y., Hirsch, A. K. H., Leysen, S., Ottmann, C., Brunsveld, L. & Milroy, L-G., 8-May-2017, In : Angewandte Chemie-International Edition. 56, 20, p. 5480-5484 5 p.

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DOI

  • Marcel Scheepstra
  • Sebastian A. Andrei
  • M. Yagiz Unver
  • Anna K. H. Hirsch
  • Seppe Leysen
  • Christian Ottmann
  • Luc Brunsveld
  • Lech-Gustav Milroy

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 coactivator recruitment. We solved the crystal structure of the spiroketal-hRXR alpha-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our cocrystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.

Original languageEnglish
Pages (from-to)5480-5484
Number of pages5
JournalAngewandte Chemie-International Edition
Volume56
Issue number20
Publication statusPublished - 8-May-2017

    Keywords

  • drug design, drug discovery, natural products, spiro compounds, structure elucidation, RETINOID-X-RECEPTOR, BIOLOGY-ORIENTED SYNTHESIS, NUCLEAR RECEPTORS, NATURAL-PRODUCTS, RXR, SCAFFOLDS, THERAPEUTICS, RECOGNITION, SELECTIVITY, RUBROMYCIN

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