Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Patnaik, Samarjit¹  Basu, Dipanwita²  Southall, Noel¹  Dehdashti, Seameen¹  Wan, Kanny K.¹  Zheng, Wei¹  Ferrer, Marc¹  Taylor, Mercedes¹  Engel, Daniel A.³  Marugan, Juan Jose¹ 

[1] NIH, Div Preclin Innovat, Natl Ctr Advancing Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA

[2] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Sch Med, 1300 Jefferson Pk Ave, Charlottesville, VA 22908 USA

[3] Alexander BioDiscoveries LLC, 530 Forrest Rd, Charlottesville, VA 22902 USA

关键词: Influenza;    NS1;    Antagonist;    Pyrazolopyridine;    Antiviral;   

DOI  :  10.1016/j.bmcl.2019.02.027

来源: Elsevier

【 摘 要 】

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-beta 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.

【 授权许可】

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