2. Academic Validation
  3. Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists

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

  • Bioorg Med Chem Lett. 2019 May 1;29(9):1113-1119. doi: 10.1016/j.bmcl.2019.02.027.
Samarjit Patnaik 1,  Dipanwita Basu 2,  Noel Southall 3,  Seameen Dehdashti 3,  Kanny K Wan 3,  Wei Zheng 3,  Marc Ferrer 3,  Mercedes Taylor 3,  Daniel A Engel 4,  Juan Jose Marugan 5
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 30852083 DOI: 10.1016/j.bmcl.2019.02.027
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.

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