Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication

Tatiana Ammosova, Colette A. Pietzsch, Yasemin Saygideger, Andrey Ilatovsky, Xionghao Lin, Andrey Ivanov, Namita Kumari, Marina Jerebtsova, Amol Kulkarni, Michael Petukhov, Aykut Üren, Alexander Bukreyev, Sergei Nekhai

    Research output: Contribution to journalArticle

    2 Scopus citations

    Abstract

    Background: Ebola virus (EBOV) infection causes severe hemorrhagic fever. EBOV transcription is controlled by host protein phosphatase 1 (PP1), which dephosphorylates VP30 protein. We previously developed 1E7-03, a compound targeting a noncatalytic site of PP1 that induced VP30 phosphorylation and inhibited EBOV transcription. Here, we attempted to further improve 1E7-03, which was not stable in murine serum. Results: High-throughput screening with EBOV-green fluorescent protein was conducted on 72 1E7-03 analogs and identified 6 best inhibitory and the least toxic compounds. A parallel in silico screening of compounds from the ZINC database by docking to PP1 identified the best-binding compound C31, which was also present among the top 6 compounds found in the viral screen. C31 showed the best EBOV inhibitory activity among the top 6 compounds and also inhibited EBOV minigenome. C31 bound to the PP1 C-terminal groove in vitro and increased VP30 phosphorylation in cultured cells. C31 demonstrated improved stability in mouse plasma and cell permeability, compared with 1E7-03. It was also detected for 24 hours after injection in mice. Conclusion: C31 represents a novel PP1-targeting EBOV inhibitor with improved pharmacological properties that can be further evaluated for future antifiloviral therapy.

    Original languageEnglish (US)
    Pages (from-to)S627-S635
    JournalThe Journal of infectious diseases
    Volume218
    Issue number5
    DOIs
    StatePublished - Nov 22 2018

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Infectious Diseases

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  • Cite this

    Ammosova, T., Pietzsch, C. A., Saygideger, Y., Ilatovsky, A., Lin, X., Ivanov, A., Kumari, N., Jerebtsova, M., Kulkarni, A., Petukhov, M., Üren, A., Bukreyev, A., & Nekhai, S. (2018). Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication. The Journal of infectious diseases, 218(5), S627-S635. https://doi.org/10.1093/infdis/jiy422