Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre of Biotherapy, Chengdu 610041, P. R. China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
J Med Chem. 2022 Aug 25;65(16):11058-11065. doi: 10.1021/acs.jmedchem.2c00289. Epub 2022 Aug 4.
Tuberculosis is caused by the bacterium () and is ranked as the second killer infectious disease after COVID-19. Proteasome accessory factor A (PafA) is considered an attractive target because of its low sequence conservation in humans and its role in virulence. In this study, we designed a mutant of PafA that enabled large-scale purification of active PafA. Using a devised high-throughput screening assay, two PafA inhibitors were discovered. ST1926 inhibited PafA by binding in the Pup binding groove, but it was less active against PafA because the ST1926-binding residues are not conserved. Bithionol bound to the conserved ATP-binding pocket, thereby, inhibits PafA in an ATP-competitive manner. Both ST1926 and bithionol inhibited the growth of an attenuated strain (H37Ra) at micromolar concentrations. Our work thus provides new tools for tuberculosis research and a foundation for future PafA-targeted drug development for treating tuberculosis.
结核病是由细菌()引起的，是继 COVID-19 之后排名第二的传染性杀手疾病。蛋白酶体辅助因子 A (PafA) 因其在人类中低序列保守性及其在毒力中的作用而被认为是一个有吸引力的靶标。在这项研究中，我们设计了一种突变体 PafA，使其能够大规模纯化活性 PafA。使用设计的高通量筛选测定法，发现了两种 PafA 抑制剂。ST1926 通过结合在 Pup 结合槽中抑制 PafA，但由于 ST1926 结合残基在人类中不保守，其对 PafA 的活性较低。双羟萘酸结合到保守的 ATP 结合口袋，从而以 ATP 竞争性方式抑制 PafA。ST1926 和双羟萘酸都以微摩尔浓度抑制减毒菌株 (H37Ra) 的生长。因此，我们的工作为结核病研究提供了新的工具，并为未来以 PafA 为靶点的治疗结核病药物的开发奠定了基础。
