鉴定一种环二核苷酸磷酸二酯酶抑制剂。
Identification of a Cyclic Dinucleotide Phosphodiesterase Inhibitor.
机构信息
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, United States.
Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
出版信息
ACS Infect Dis. 2021 Feb 12;7(2):309-317. doi: 10.1021/acsinfecdis.0c00444. Epub 2021 Jan 25.
Immune cells sense bacteria-derived c-di-GMP and c-di-AMP as well as host-derived cGAMP, which is synthesized by cGAS upon binding to the pathogen's DNA, to mount an immunological response (cytokine production) via the STING-TBK1 pathway. Successful pathogens, such as and group B streptococcus, harbor phosphodiesterases (PDEs) that can cleave bacterial c-di-AMP as well as host-derived cGAMP to blunt the host's response to infection. Selective inhibitors of bacterial cyclic dinucleotide (CDN) PDEs are needed as tool compounds to study the role(s) of CDN PDEs during infection and they could also become bona fide antivirulence compounds, but there is a paucity of such compounds. Using a high-throughput assay, we identified six inhibitors of MTB CDN PDE (CdnP). The most potent inhibitor, with an IC of ∼18 μM, did not inhibit the enzymatic activities of three other bacterial CDN PDEs (Yybt, RocR, and GBS-CdnP), a viral CDN PDE (poxin) or mammalian ENPP1.
免疫细胞可以感知细菌衍生的 c-di-GMP 和 c-di-AMP 以及宿主衍生的 cGAMP，cGAS 在与病原体 DNA 结合后会合成 cGAMP，通过 STING-TBK1 途径引发免疫反应（细胞因子产生）。成功的病原体，如 和 B 组链球菌，携带有磷酸二酯酶（PDEs），可以切割细菌 c-di-AMP 以及宿主衍生的 cGAMP，从而削弱宿主对感染的反应。需要选择性抑制细菌环二核苷酸（CDN）PDE 的抑制剂作为工具化合物来研究 CDN PDE 在感染过程中的作用，它们也可能成为真正的抗毒力化合物，但目前这类化合物很少。我们使用高通量测定法鉴定了六种 MTB CDN PDE（CdnP）的抑制剂。最有效的抑制剂 ，IC 约为 18 μM，不抑制三种其他细菌 CDN PDE（Yybt、RocR 和 GBS-CdnP）、一种病毒 CDN PDE（poxin）或哺乳动物 ENPP1 的酶活性。
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