小柯机器人

2022年6月3日，《细胞》杂志在线发表了奥地利分子病理学研究所Tim Clausen、德国杜伊斯堡-埃森大学Markus Kaiser等研究人员的合作成果。该研究开发出BacPROTAC技术，实现细菌中的靶向蛋白降解。

研究人员开发了小分子降解剂，即所谓的BacPROTAC，它与ClpC:ClpP蛋白酶的底物受体结合，为新底物的降解打下基础。除了它们的靶向功能外，BacPROTAC还激活ClpC，将静止的解折叠酶转化为其功能状态。诱导的高阶低聚物通过低温电镜分析被可视化，这提供了激活的ClpC展开蛋白质底物的结构快照。

最后，在分枝杆菌中进行的药物敏感性和降解试验证明了BacPROTAC的体内活性，其能够通过与已建立的降解决定子融合来选择性地瞄准内源性蛋白质。除了指导抗生素的发现外，BacPROTAC技术还提供了一个多功能的研究工具，使细菌蛋白质的诱导性降解成为可能。

据介绍，劫持细胞蛋白降解系统为药物发现提供了独特的机会，蛋白分解-靶向嵌合体就是一个例子。尽管它们在医学化学上有很大的前景，但到目前为止，还不可能对细菌降解机制进行重新编程来干扰微生物感染。

附：英文原文

Title: BacPROTACs mediate targeted protein degradation in bacteria

Author: Francesca E. Morreale, Stefan Kleine, Julia Leodolter, Sabryna Junker, David M. Hoi, Stepan Ovchinnikov, Anastasia Okun, Juliane Kley, Robert Kurzbauer, Lukas Junk, Somraj Guha, David Podlesainski, Uli Kazmaier, Guido Boehmelt, Harald Weinstabl, Klaus Rumpel, Volker M. Schmiedel, Markus Hartl, David Haselbach, Anton Meinhart, Markus Kaiser, Tim Clausen

Issue&Volume: 2022-06-03

Abstract: Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, so far, it has not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, allowing selective targeting of endogenous proteins via fusion to an established degron. In addition to guiding antibiotic discovery, the BacPROTAC technology presents a versatile research tool enabling the inducible degradation of bacterial proteins.

DOI: 10.1016/j.cell.2022.05.009

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00593-1