Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Chem Biol. 2022 Jul 21;29(7):1126-1139.e12. doi: 10.1016/j.chembiol.2022.03.006. Epub 2022 Mar 22.
Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity. Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (ΔPPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice. SMIP-30 provides proof of concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.
金属依赖性蛋白磷酸酶 (PPMs) 在多种细胞过程中发挥着重要作用，包括炎症、增殖、分化和应激反应等，这些在癌症和代谢性疾病中都得到了深入研究。针对 PPMs 来调节宿主免疫以应对病原体是一个雄心勃勃的提议。由于开发针对 PPMs 的抑制剂具有挑战性且选择性差，因此这种策略的可行性尚未得到证实。我们结合仿生模块化策略和面向功能的合成，设计、合成和筛选了超过 500 种拟天然产物，从而发现了一种针对 PPM1A 的有效、选择性和非细胞毒性的小分子抑制剂 SMIP-30。SMIP-30 抑制 PPM1A 或其基因缺失（ΔPPM1A）通过依赖于 p62-SQSTM1 磷酸化的机制激活自噬，从而限制了结核分枝杆菌在巨噬细胞和感染小鼠肺部中的细胞内存活。SMIP-30 提供了 PPMs 可成药的概念验证，并为开发针对结核病的宿主导向治疗提供了有希望的靶点。
