新型吡唑并吡啶流感病毒非结构蛋白 1 拮抗剂的鉴定、设计与合成。
Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists.
机构信息
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, 1300 Jefferson Park Ave., Charlottesville, VA 22908, United States.
出版信息
Bioorg Med Chem Lett. 2019 May 1;29(9):1113-1119. doi: 10.1016/j.bmcl.2019.02.027. Epub 2019 Feb 26.
Abstract
Nonstructural protein 1 (NS1) plays a crucial function in the replication, spread, and pathogenesis of influenza virus by inhibiting the host innate immune response. Here we report the discovery and optimization of novel pyrazolopyridine NS1 antagonists that can potently inhibit influenza A/PR/8/34 replication in MDCK cells, rescue MDCK cells from cytopathic effects of seasonal influenza A strains, reverse NS1-dependent inhibition of IFN-β gene expression, and suppress the slow growth phenotype in NS1-expressing yeast. These pyrazolopyridines will enable researchers to investigate NS1 function during infection and how antagonists can be utilized in the next generation of treatments for influenza infection.
摘要
非结构蛋白 1（NS1）通过抑制宿主固有免疫反应，在流感病毒的复制、传播和发病机制中发挥关键作用。在这里，我们报告了新型吡唑并吡啶 NS1 拮抗剂的发现和优化，这些拮抗剂能够在 MDCK 细胞中有效抑制流感 A/PR/8/34 的复制，挽救 MDCK 细胞免受季节性流感 A 株的细胞病变效应，逆转 NS1 依赖性 IFN-β 基因表达抑制，并抑制在表达 NS1 的酵母中的缓慢生长表型。这些吡唑并吡啶类化合物将使研究人员能够研究感染过程中的 NS1 功能，以及拮抗剂如何在下一代流感感染治疗中得到应用。
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