Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists. Issue 9 (1st May 2019)

• Record Type: Journal Article
• Authors: Patnaik, Samarjit; Basu, Dipanwita; Southall, Noel; Dehdashti, Seameen; Wan, Kanny K.; Zheng, Wei; Ferrer, Marc; Taylor, Mercedes; Engel, Daniel A.; Marugan, Juan Jose
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 9(2019)
• Page Start: 1113
• Page End: 1119
• Publication Date: 2019-05-01
• Subjects: ZXQUYTHURXXUPT-UHFFFAOYSA-N -- NPDYBEJUGJIPPR-UHFFFAOYSA-N -- YBRHGNCGFMRGSV-UHFFFAOYSA-N; Influenza -- NS1 -- Antagonist -- Pyrazolopyridine -- Antiviral; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.027
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Novel pyrazolopyridine NS1-antagonists for influenza A. Reduces viral titer by 128-fold at 10 μM. Inhibits cytopathic effects of a seasonal influenza A strain (EC50 = 660 nM) Restores IFN-β mRNA levels in virus-infected MDCK cells. Pharmacokinetics: > 1 μM concentration in lungs for over 12 h after 30 mpk IP single dose in mouse. 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.