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Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity.

Andreas M Voll1, Christian Meyners1, Martha C Taubert1

  • 1Department Chemistry and Biochemistry, Clemens-Schöpf-Institute, Technical University Darmstadt, Alarich-Weiss Strasse 4, 64287, Darmstadt, Germany.

Angewandte Chemie (International Ed. in English)
|April 12, 2021
PubMed
Summary

New macrocycles show unprecedented selectivity for FKBP51 over related proteins. This discovery offers a novel chemical scaffold for developing targeted FKBP51 drugs, avoiding immunosuppression and blocking cellular effects.

Keywords:
FKBP51immunophilinmacrocyclesubtype selectivitytransient binding pocket

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Area of Science:

  • Drug discovery
  • Chemical biology
  • Structural biology

Background:

  • FKBP51 is an attractive drug target, but achieving subtype selectivity is challenging.
  • Existing FKBP51 ligands poorly discriminate against FKBP12 and FKBP12.6 homologs.
  • Developing selective FKBP51 inhibitors is crucial for therapeutic applications.

Purpose of the Study:

  • To discover novel FKBP51 ligands with enhanced subtype selectivity.
  • To elucidate the binding mode and structural basis for selectivity.
  • To validate the cellular engagement and functional effects of new ligands.

Main Methods:

  • Macrocyclization of existing FKBP51 ligands.
  • Structural studies (X-ray crystallography) to determine binding modes.
  • Conformation-sensitive assays to assess binding in solution.
  • Cellular assays to evaluate target engagement and functional effects.

Main Results:

  • Macrocyclic analogs exhibited unexpected high selectivity for FKBP51 over FKBP12 and FKBP12.6.
  • A novel binding mode involving a transient conformation, disfavored in small FKBPs, was identified.
  • This binding mode was confirmed to occur in solution for the new macrocyclic class.
  • The discovered macrocycles were non-immunosuppressive, engaged FKBP51 in cells, and inhibited FKBP51's effect on IKKα.

Conclusions:

  • A new class of macrocyclic compounds provides a promising scaffold for selective FKBP51 ligands.
  • The unique binding mode explains the enhanced selectivity against FKBP12 and FKBP12.6.
  • These findings pave the way for developing non-immunosuppressive FKBP51-targeted therapeutics.