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

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.

SUBMITTER: Patnaik S

PROVIDER: S-EPMC8290212 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Patnaik Samarjit S Basu Dipanwita D Southall Noel N Dehdashti Seameen S Wan Kanny K KK Zheng Wei W Ferrer Marc M Taylor Mercedes M Engel Daniel A DA Marugan Juan Jose JJ

Bioorganic & medicinal chemistry letters 20190226 9

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 ...[more]

PMID: 30852083

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