Walther Raoul, Westermann Linda M, Carmali Sheiliza, Jackson Sophie E, Brötz-Oesterhelt Heike, Spring David R
Yusuf Hamied Department of Chemistry, University of Cambridge Lensfield Road CB2 1EW Cambridge UK
Interfaculty Institute of Microbiology and Infection Medicine, Dept. of Bioactive Compounds, University of Tübingen Auf der Morgenstelle 28 72076 Tübingen Germany
RSC Med Chem. 2023 May 17;14(6):1186-1191. doi: 10.1039/d3md00136a. eCollection 2023 Jun 22.
The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.
酪蛋白水解蛋白酶复合体ClpXP是原核生物中一种重要的管家酶，负责去除和降解错误折叠及聚集的蛋白质，并进行调节性蛋白水解。事实证明，其功能失调，特别是通过抑制或变构激活蛋白水解核心ClpP，是一种降低毒力和根除持续性细菌感染的有前景的策略。在此，我们报告了一种合理的药物设计方法，以鉴定能增强ClpP蛋白水解作用的大环肽。这项工作扩展了对ClpP动力学的理解，并通过化学方法揭示了其伴侣蛋白ClpX对其构象的控制作用。所鉴定的大环肽配体未来可能作为开发用于抗菌应用的ClpP激活剂的起点。
