光开关抑制剂光控制特定激酶活性

IF 3.8 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tim Aguirre, Ellen Teichmann, Florian Q. Römpp, Ruthey Vivier, Cole Bryant, Matthew A. Hulverson, Wesley C. Van Voorhis, Kayode K. Ojo, J. Stone Doggett, Dorothea Fiedler* and Stefan Hecht*, 
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引用次数: 0

摘要

有效和选择性的小分子抑制剂是阐明复杂信号网络中蛋白激酶功能的有价值的工具。在抑制剂支架中加入可光切换的片段提供了以时间精度控制抑制剂效力的机会,而选择性抑制的挑战通常可以通过采用化学遗传方法(称为类似物敏感方法)来解决。在这里,我们结合了这两种方法的优点,并报道了可光敏偶氮唑靶向刚地弓形虫钙依赖性蛋白激酶1 (CDPK1),由于其甘氨酸看门人残基,这种激酶对类似物敏感的激酶抑制剂天然敏感。最有前途的偶氮唑具有良好的光化学性质、热稳定性和两种光稳态之间的IC50值的显著差异。因此,CDPK1激酶反应可以通过施加不同波长的光来动态和可逆地控制。偶氮唑对CDPK1的抑制很大程度上依赖于看门人残基的性质,因为看门人大小的连续增加会导致抑制活性的同时丧失。此外,在细胞培养模型中,两种光开关抑制剂对弓形虫和小隐孢子虫感染表现出活性,使它们成为分析CDPK1在高时间控制的感染周期中的作用的有希望的工具箱。总的来说,这项工作结合了类似物敏感方法和光药理学的优点,而不影响抑制效力,因此在未来应用于其他蛋白激酶方面具有很大的前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Photoswitchable Inhibitors to Optically Control Specific Kinase Activity

Photoswitchable Inhibitors to Optically Control Specific Kinase Activity

Potent and selective small-molecule inhibitors are valuable tools to elucidate the functions of protein kinases within complex signaling networks. Incorporation of a photoswitchable moiety into the inhibitor scaffold offers the opportunity to steer inhibitor potency with temporal precision, while the challenge of selective inhibition can often be addressed by employing a chemical genetic approach, termed the analog-sensitive method. Here, we combine the perks of these two approaches and report photoswitchable azopyrazoles to target calcium-dependent protein kinase 1 (CDPK1) from Toxoplasma gondii, a kinase naturally susceptible to analog-sensitive kinase inhibitors due to its glycine gatekeeper residue. The most promising azopyrazoles display favorable photochemical properties, thermal stability, and a substantial difference in IC50 values between both photostationary states. Consequently, the CDPK1 kinase reaction can be controlled dynamically and reversibly by applying light of different wavelengths. Inhibition of CDPK1 by the azopyrazoles drastically relies on the nature of the gatekeeper residue as a successive increase in gatekeeper size causes a concurrent loss of inhibitory activity. Furthermore, two photoswitchable inhibitors exhibit activity against T. gondii and Cryptosporidium parvum infection in a cell culture model, making them a promising addition to the toolbox for dissecting the role of CDPK1 in the infectious cycle with high temporal control. Overall, this work merges the benefits of the analog-sensitive approach and photopharmacology without compromising inhibitory potency and thus holds great promise for application to other protein kinases in the future.

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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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