A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication

Priya Luthra, Jue Liang, Colette A. Pietzsch, Sudip Khadka, Megan R. Edwards, Shuguang Wei, Sampriti De, Bruce Posner, Alexander Bukreyev, Joseph M. Ready, Christopher F. Basler

    Research output: Contribution to journalArticle

    • 4 Citations

    Abstract

    Ebola virus (EBOV) is an enveloped negative-sense, single-stranded RNA virus of the filovirus family that causes severe disease in humans. Approved therapies for EBOV disease are lacking. EBOV RNA synthesis is carried out by a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are therefore potential antiviral targets. To identify potential lead inhibitors of EBOV RNA synthesis, a library of small molecule compounds was screened against a previously established assay of EBOV RNA synthesis, the EBOV minigenome assay (MGA), in 384 well microplate format. The screen identified 56 hits that inhibited EBOV MGA activity by more than 70% while exhibiting less than 20% cell cytotoxicity. Inhibitory chemical scaffolds included angelicin derivatives, derivatives of the antiviral compound GSK983 and benzoquinolines. Structure-activity relationship (SAR) studies of the benzoquinoline scaffold produced ∼50 analogs and led to identification of an optimized compound, SW456, with a submicromolar IC50 in the EBOV MGA and antiviral activity against infectious EBOV in cell culture. The compound was also active against a MGA for another deadly filovirus, Marburg virus. It also exhibited antiviral activity towards a negative-sense RNA virus from the rhabdovirus family, vesicular stomatitis virus, and a positive-sense RNA virus, Zika virus. Overall, these data demonstrate the potential of the EBOV MGA to identify anti-EBOV compounds and identifies the benzoquinoline series as a broad-spectrum antiviral lead.

    LanguageEnglish (US)
    Pages193-201
    Number of pages9
    JournalAntiviral Research
    Volume150
    DOIs
    StatePublished - Feb 1 2018

    Fingerprint

    Ebolavirus
    Virus Replication
    Antiviral Agents
    RNA Viruses
    RNA
    Ebola Hemorrhagic Fever
    Marburgvirus
    Rhabdoviridae
    Small Molecule Libraries
    Viruses
    RNA Replicase
    Vesicular Stomatitis
    Structure-Activity Relationship
    Inhibitory Concentration 50
    Cell Culture Techniques

    Keywords

    • Antiviral
    • Ebola virus
    • Filovirus
    • Marburg virus
    • Vesicular stomatitis virus
    • Zika virus

    ASJC Scopus subject areas

    • Pharmacology
    • Virology

    Cite this

    Luthra, P., Liang, J., Pietzsch, C. A., Khadka, S., Edwards, M. R., Wei, S., ... Basler, C. F. (2018). A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication. Antiviral Research, 150, 193-201. https://doi.org/10.1016/j.antiviral.2017.12.019

    A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication. / Luthra, Priya; Liang, Jue; Pietzsch, Colette A.; Khadka, Sudip; Edwards, Megan R.; Wei, Shuguang; De, Sampriti; Posner, Bruce; Bukreyev, Alexander; Ready, Joseph M.; Basler, Christopher F.

    In: Antiviral Research, Vol. 150, 01.02.2018, p. 193-201.

    Research output: Contribution to journalArticle

    Luthra, P, Liang, J, Pietzsch, CA, Khadka, S, Edwards, MR, Wei, S, De, S, Posner, B, Bukreyev, A, Ready, JM & Basler, CF 2018, 'A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication' Antiviral Research, vol. 150, pp. 193-201. https://doi.org/10.1016/j.antiviral.2017.12.019
    Luthra, Priya ; Liang, Jue ; Pietzsch, Colette A. ; Khadka, Sudip ; Edwards, Megan R. ; Wei, Shuguang ; De, Sampriti ; Posner, Bruce ; Bukreyev, Alexander ; Ready, Joseph M. ; Basler, Christopher F. / A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication. In: Antiviral Research. 2018 ; Vol. 150. pp. 193-201.
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    abstract = "Ebola virus (EBOV) is an enveloped negative-sense, single-stranded RNA virus of the filovirus family that causes severe disease in humans. Approved therapies for EBOV disease are lacking. EBOV RNA synthesis is carried out by a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are therefore potential antiviral targets. To identify potential lead inhibitors of EBOV RNA synthesis, a library of small molecule compounds was screened against a previously established assay of EBOV RNA synthesis, the EBOV minigenome assay (MGA), in 384 well microplate format. The screen identified 56 hits that inhibited EBOV MGA activity by more than 70{\%} while exhibiting less than 20{\%} cell cytotoxicity. Inhibitory chemical scaffolds included angelicin derivatives, derivatives of the antiviral compound GSK983 and benzoquinolines. Structure-activity relationship (SAR) studies of the benzoquinoline scaffold produced ∼50 analogs and led to identification of an optimized compound, SW456, with a submicromolar IC50 in the EBOV MGA and antiviral activity against infectious EBOV in cell culture. The compound was also active against a MGA for another deadly filovirus, Marburg virus. It also exhibited antiviral activity towards a negative-sense RNA virus from the rhabdovirus family, vesicular stomatitis virus, and a positive-sense RNA virus, Zika virus. Overall, these data demonstrate the potential of the EBOV MGA to identify anti-EBOV compounds and identifies the benzoquinoline series as a broad-spectrum antiviral lead.",
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