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Bioorg Med Chem Lett. 2019 Feb 26. pii: S0960-894X(19)30111-8. doi: 10.1016/j.bmcl.2019.02.027. [Epub ahead of print]

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

Author information

1
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: patnaiks@mail.nih.gov.
2
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, 1300 Jefferson Park Ave., Charlottesville, VA 22908, United States.
3
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
4
Alexander BioDiscoveries, LLC, 530 Forrest Rd., Charlottesville, VA 22902, United States. Electronic address: dae2s@virginia.edu.
5
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: maruganj@mail.nih.gov.

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.

KEYWORDS:

Antagonist; Antiviral; Influenza; NS1; Pyrazolopyridine

PMID:
30852083
DOI:
10.1016/j.bmcl.2019.02.027

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