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Bifunctional thiosialosides inhibit influenza virus.

ABSTRACT: We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as inhibitors of influenza virus. These first generation compounds show IC50 values ranging from low micromolar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influenza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68).

SUBMITTER: Yang Y

PROVIDER: S-EPMC4397911 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Bifunctional thiosialosides inhibit influenza virus.

Yang Yang Y He Yun Y Li Xingzhe X Dinh Hieu H Iyer Suri S SS

Bioorganic & medicinal chemistry letters 20131211 2

We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as inhibitors of influenza virus. These first generation compounds show IC50 values ranging from low micromolar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influenza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68). ...[more]

PMID: 24374271

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Project description:BackgroundDouble-stranded RNA dependent protein kinase (PKR) is a key regulator of the anti-viral innate immune response in mammalian cells. PKR activity is regulated by a 58 kilo Dalton cellular inhibitor (P58(IPK)), which is present in inactive state as a complex with Hsp40 under normal conditions. In case of influenza A virus (IAV) infection, P58(IPK) is known to dissociate from Hsp40 and inhibit PKR activation. However the influenza virus component responsible for PKR inhibition through P58(IPK) activation was hitherto unknown.Principal findingsHuman heat shock 40 protein (Hsp40) was identified as an interacting partner of Influenza A virus nucleoprotein (IAV NP) using a yeast two-hybrid screen. This interaction was confirmed by co-immunoprecipitation studies from mammalian cells transfected with IAV NP expressing plasmid. Further, the IAV NP-Hsp40 interaction was validated in mammalian cells infected with various seasonal and pandemic strains of influenza viruses. Cellular localization studies showed that NP and Hsp40 co-localize primarily in the nucleus. During IAV infection in mammalian cells, expression of NP coincided with the dissociation of P58(IPK) from Hsp40 and decrease PKR phosphorylation. We observed that, plasmid based expression of NP in mammalian cells leads to decrease in PKR phosphorylation. Furthermore, inhibition of NP expression during influenza virus replication led to PKR activation and concomitant increase in eIF2α phosphorylation. Inhibition of NP expression also led to reduced IRF3 phosphorylation, enhanced IFN β production and concomitant reduction of virus replication. Taken together our data suggest that NP is the viral factor responsible for P58(IPK) activation and subsequent inhibition of PKR-mediated host response during IAV infection.SignificanceOur findings demonstrate a novel role of IAV NP in inhibiting PKR-mediated anti-viral host response and help us understand P58(IPK) mediated inhibition of PKR activity during IAV infection.

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Bifunctional thiosialosides inhibit influenza virus.

Publications

Bifunctional thiosialosides inhibit influenza virus.

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