Photoswitchable epothilone-based microtubule stabilisers allow GFP-imaging-compatible, optical control over the microtubule cytoskeleton
Gao, Li; Meiring, Joyce C M; Heise, Constanze; Rai, Ankit; Müller-Deku, Adrian; Akhmanova, Anna; Thorn-Seshold, Julia; Thorn-Seshold, Oliver
(2022) Angewandte Chemie-International Edition, volume 61, issue 10, pp. 1 - 11
(Article)
Abstract
Optical methods to modulate microtubule dynamics show promise for reaching the micron- and millisecond-scale resolution needed to decrypt the roles of the cytoskeleton in biology. However, optical microtubule stabilisers are under-developed. We introduce “STEpos” as GFP-orthogonal, light-responsive epothilone-based microtubule stabilisers. They use a novel styrylthiazole photoswitch in a design to
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modulate hydrogen-bonding and steric effects that control epothilone potency. STEpos photocontrol microtubule dynamics and cell division with micron- and second-scale spatiotemporal precision. They substantially improve potency, solubility, and ease-of-use compared to previous optical microtubule stabilisers, and the structure-photoswitching-activity relationship insights in this work will guide future optimisations. The STEpo reagents can contribute greatly to high-precision research in cytoskeleton biophysics, cargo transport, cell motility, cell division, development, and neuroscience.
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Keywords: Bioorganic Chemistry, Microtubule Inhibitor, Natural Products, Photopharmacology, Photoswitch, Catalysis, General Chemistry
ISSN: 1433-7851
Publisher: John Wiley and Sons Ltd
Note: Funding Information: We thank Jan Huebner (Bayer) for the gift of EpoB, Dirk Trauner (NYU) for collegial discussions and for securing the EpoB, Monique Preusse for early cell viability testing, Rebekkah Hammar for performing the tubulin polymerisation assay, Maximilian Wranik and Michel O. Steinmetz (PSI Villigen) for attempting crystallisation, and Martin Reynders for the Schrödinger visualisation models in Figure S1. We thank Reviewer 2 for suggesting the expression . We are grateful to Henrietta Lacks, now deceased, and to her surviving family members for their contributions to biomedical research. O.T.‐S. thanks the German Research Foundation (DFG: Emmy Noether grant number 400324123; SFB 1032 project B09 number 201269156; SFB TRR 152 project P24 number 239283807; SPP 1926 project number 426018126) for funding support. J.C.M.M. acknowledges support from an EMBO Long Term Fellowship. J.T.‐S. thanks the Joachim Herz Stiftung for a Translational Research Fellowship. Open Access funding enabled and organized by Projekt DEAL. optical transparency Funding Information: We thank Jan Huebner (Bayer) for the gift of EpoB, Dirk Trauner (NYU) for collegial discussions and for securing the EpoB, Monique Preusse for early cell viability testing, Rebekkah Hammar for performing the tubulin polymerisation assay, Maximilian Wranik and Michel O. Steinmetz (PSI Villigen) for attempting crystallisation, and Martin Reynders for the Schrödinger visualisation models in Figure S1. We thank Reviewer 2 for suggesting the expression optical transparency. We are grateful to Henrietta Lacks, now deceased, and to her surviving family members for their contributions to biomedical research. O.T.-S. thanks the German Research Foundation (DFG: Emmy Noether grant number 400324123; SFB 1032 project B09 number 201269156; SFB TRR 152 project P24 number 239283807; SPP 1926 project number 426018126) for funding support. J.C.M.M. acknowledges support from an EMBO Long Term Fellowship. J.T.-S. thanks the Joachim Herz Stiftung for a Translational Research Fellowship. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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