2. Academic Validation
  3. High-Throughput Screening Assay to Identify Small Molecule Inhibitors of Marburg Virus VP40 Protein

High-Throughput Screening Assay to Identify Small Molecule Inhibitors of Marburg Virus VP40 Protein

  • ACS Infect Dis. 2020 Oct 9;6(10):2783-2799. doi: 10.1021/acsinfecdis.0c00512.
Priya Luthra 1,  Manu Anantpadma 2,  Sampriti De 3,  Julien Sourimant 4,  Robert A Davey 5,  Richard K Plemper 4,  Christopher F Basler 3
Affiliations

Affiliations

  • 1 Trudeau Institute, Saranac Lake, New York 12983-2100, United States.
  • 2 WuXi App Tec, Philadelphia, Pennsylvania 19112, United States.
  • 3 Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302-3965, United States.
  • 4 Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia 30302-3965, United States.
  • 5 National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, Massachusetts 02118, United States.
PMID: 32870648 DOI: 10.1021/acsinfecdis.0c00512
Abstract

Marburg virus (MARV) causes sporadic outbreaks of severe disease with high case fatality rates in humans. To date, neither therapeutics nor prophylactic approaches have been approved for MARV disease. The MARV matrix protein VP40 (mVP40) plays central roles in virus assembly and budding. mVP40 also inhibits interferon signaling by inhibiting the function of Janus kinase 1. This suppression of host Antiviral defenses likely contributes to MARV virulence and therefore is a potential therapeutic target. We developed and optimized a cell-based high-throughput screening (HTS) assay in 384-well format to measure mVP40 interferon (IFN) antagonist function such that inhibitors could be identified. We performed a pilot screen of 1280 bioactive compounds and identified 3 hits, azaguanine-8, tosufloxacin hydrochloride, and linezolid, with Z scores > 3 and no significant cytotoxicity. Of these, azaguanine-8 inhibited MARV growth at noncytotoxic concentrations. These data demonstrate the suitability of the HTS mVP40 assay for drug discovery and suggest potential directions for anti-MARV therapeutic development.

Keywords

Marburg virus; VP40 protein; high-throughput screen; interferon signaling.

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