High-Throughput Screening Assay to Identify Small Molecule Inhibitors of Marburg Virus VP40 Protein.
Priya LuthraManu AnantpadmaSampriti DeJulien SourimantRobert A DaveyRichard K PlemperChristopher F BaslerPublished in: ACS infectious diseases (2020)
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.
Keyphrases
- small molecule
- high throughput
- disease virus
- drug discovery
- protein protein
- dendritic cells
- single cell
- escherichia coli
- signaling pathway
- pseudomonas aeruginosa
- immune response
- amino acid
- binding protein
- late onset
- stem cells
- risk assessment
- cell therapy
- human health
- mesenchymal stem cells
- cystic fibrosis
- bone marrow
- protein kinase
- machine learning
- infectious diseases
- candida albicans
- amyotrophic lateral sclerosis