A Robust, GFP-Orthogonal Photoswitchable Inhibitor Scaffold Extends Optical Control over the Microtubule Cytoskeleton
A Robust, GFP-Orthogonal Photoswitchable Inhibitor Scaffold Extends Optical Control over the Microtubule Cytoskeleton
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DOI：
10.1016/j.chembiol.2020.11.007
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发表时间：
2021-02-18
影响因子：
8.6
通讯作者：
Thorn-Seshold, Oliver
中科院分区：
文献类型：
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作者：
Gao, Li;Meiring, Joyce C. M.;Thorn-Seshold, Oliver
光学控制的化学试剂，被称为“药物”，是精确时空控制蛋白质的强大工具，特别是当基因敲除或光遗传学等遗传方法不可行时。然而，目前的药物支架，如偶氮苯是不耐受的GFP/YFP成像和代谢不稳定，造成严重的限制，为生物用途。我们合理地设计了一种光开关“SBT”支架来克服这些问题，然后将其衍生化以产生异常代谢稳健和完全GFP/YFP正交的“SBTub”药物微管蛋白抑制剂。先导化合物SBTub 3允许微管动力学、组织和微管依赖性过程的时间可逆的、细胞精确的、甚至亚细胞精确的光调节。通过克服以前的微管药物的局限性，SBTubs在细胞生物学中提供了强大的应用，并且它们的鲁棒性和药物样性有利于体内应用中的细胞内生物控制。我们还期望SBT支架的鲁棒性和成像正交性将激发其他衍生化，其旨在扩展一系列其他生物靶标的光控。
Optically controlled chemical reagents, termed "photopharmaceuticals,'' are powerful tools for precise spatiotemporal control of proteins particularly when genetic methods, such as knockouts or optogenetics are not viable options. However, current photopharmaceutical scaffolds, such as azobenzenes are intolerant of GFP/YFP imaging and are metabolically labile, posing severe limitations for biological use. We rationally designed a photoswitchable "SBT" scaffold to overcome these problems, then derivatized it to create exceptionally metabolically robust and fully GFP/YFP-orthogonal "SBTub" photopharmaceutical tubulin inhibitors. Lead compound SBTub3 allows temporally reversible, cell-precise, and even subcellularly precise photomodulation of microtubule dynamics, organization, and microtubule-dependent processes. By overcoming the previous limitations of microtubule photopharmaceuticals, SBTubs offer powerful applications in cell biology, and their robustness and druglikeness are favorable for intracellular biological control in in vivo applications. We furthermore expect that the robustness and imaging orthogonality of the SBT scaffold will inspire other derivatizations directed at extending the photocontrol of a range of other biological targets.