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 Citations (Scopus)

    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

    Fingerprint

    Ebolavirus
    Protein Phosphatase 1
    Virus Replication
    Ebola Hemorrhagic Fever
    Phosphorylation
    Poisons
    Phosphoprotein Phosphatases
    Green Fluorescent Proteins
    Plasma Cells
    Computer Simulation
    Cultured Cells
    Permeability
    Fever
    Databases
    Pharmacology
    Injections
    Serum

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Infectious Diseases

    Cite this

    Ammosova, T., Pietzsch, C. A., Saygideger, Y., Ilatovsky, A., Lin, X., Ivanov, 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

    Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication. / Ammosova, Tatiana; Pietzsch, Colette A.; Saygideger, Yasemin; Ilatovsky, Andrey; Lin, Xionghao; Ivanov, Andrey; Kumari, Namita; Jerebtsova, Marina; Kulkarni, Amol; Petukhov, Michael; Üren, Aykut; Bukreyev, Alexander; Nekhai, Sergei.

    In: The Journal of infectious diseases, Vol. 218, No. 5, 22.11.2018, p. S627-S635.

    Research output: Contribution to journalArticle

    Ammosova, T, Pietzsch, CA, 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, vol. 218, no. 5, pp. S627-S635. https://doi.org/10.1093/infdis/jiy422
    Ammosova T, Pietzsch CA, Saygideger Y, Ilatovsky A, Lin X, Ivanov A et al. Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication. The Journal of infectious diseases. 2018 Nov 22;218(5):S627-S635. https://doi.org/10.1093/infdis/jiy422
    Ammosova, Tatiana ; Pietzsch, Colette A. ; Saygideger, Yasemin ; Ilatovsky, Andrey ; Lin, Xionghao ; Ivanov, Andrey ; Kumari, Namita ; Jerebtsova, Marina ; Kulkarni, Amol ; Petukhov, Michael ; Üren, Aykut ; Bukreyev, Alexander ; Nekhai, Sergei. / Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication. In: The Journal of infectious diseases. 2018 ; Vol. 218, No. 5. pp. S627-S635.
    @article{bf8e745bbb01489190de60e3df96c4f6,
    title = "Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication",
    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.",
    author = "Tatiana Ammosova and Pietzsch, {Colette A.} and Yasemin Saygideger and Andrey Ilatovsky and Xionghao Lin and Andrey Ivanov and Namita Kumari and Marina Jerebtsova and Amol Kulkarni and Michael Petukhov and Aykut {\"U}ren and Alexander Bukreyev and Sergei Nekhai",
    year = "2018",
    month = "11",
    day = "22",
    doi = "10.1093/infdis/jiy422",
    language = "English (US)",
    volume = "218",
    pages = "S627--S635",
    journal = "Journal of Infectious Diseases",
    issn = "0022-1899",
    publisher = "Oxford University Press",
    number = "5",

    }

    TY - JOUR

    T1 - Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication

    AU - Ammosova, Tatiana

    AU - Pietzsch, Colette A.

    AU - Saygideger, Yasemin

    AU - Ilatovsky, Andrey

    AU - Lin, Xionghao

    AU - Ivanov, Andrey

    AU - Kumari, Namita

    AU - Jerebtsova, Marina

    AU - Kulkarni, Amol

    AU - Petukhov, Michael

    AU - Üren, Aykut

    AU - Bukreyev, Alexander

    AU - Nekhai, Sergei

    PY - 2018/11/22

    Y1 - 2018/11/22

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85057155054&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85057155054&partnerID=8YFLogxK

    U2 - 10.1093/infdis/jiy422

    DO - 10.1093/infdis/jiy422

    M3 - Article

    C2 - 30169869

    AN - SCOPUS:85057155054

    VL - 218

    SP - S627-S635

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 5

    ER -