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Iminosugars: A host-targeted approach to combat Flaviviridae infections.

ABSTRACT: N-linked glycosylation is the most common form of protein glycosylation and is required for the proper folding, trafficking, and/or receptor binding of some host and viral proteins. As viruses lack their own glycosylation machinery, they are dependent on the host's machinery for these processes. Certain iminosugars are known to interfere with the N-linked glycosylation pathway by targeting and inhibiting ?-glucosidases I and II in the endoplasmic reticulum (ER). Perturbing ER ?-glucosidase function can prevent these enzymes from removing terminal glucose residues on N-linked glycans, interrupting the interaction between viral glycoproteins and host chaperone proteins that is necessary for proper folding of the viral protein. Iminosugars have demonstrated broad-spectrum antiviral activity in vitro and in vivo against multiple viruses. This review discusses the broad activity of iminosugars against Flaviviridae. Iminosugars have shown favorable activity against multiple members of the Flaviviridae family in vitro and in murine models of disease, although the activity and mechanism of inhibition can be virus-specfic. While iminosugars are not currently approved for the treatment of viral infections, their potential use as future host-targeted antiviral (HTAV) therapies continues to be investigated.

SUBMITTER: Evans DeWald L

PROVIDER: S-EPMC7405907 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Iminosugars: A host-targeted approach to combat Flaviviridae infections.

Evans DeWald Lisa L Starr Chloe C Butters Terry T Treston Anthony A Warfield Kelly L KL

Antiviral research 20200805

N-linked glycosylation is the most common form of protein glycosylation and is required for the proper folding, trafficking, and/or receptor binding of some host and viral proteins. As viruses lack their own glycosylation machinery, they are dependent on the host's machinery for these processes. Certain iminosugars are known to interfere with the N-linked glycosylation pathway by targeting and inhibiting α-glucosidases I and II in the endoplasmic reticulum (ER). Perturbing ER α-glucosidase funct ...[more]

PMID: 32768411

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Project description:The Flaviviridae are a family of viruses that cause severe human diseases. For example, dengue virus (DENV) is a rapidly emerging pathogen causing an estimated 100 million symptomatic infections annually worldwide. No approved antivirals are available to date and clinical trials with a tetravalent dengue vaccine showed disappointingly low protection rates. Hepatitis C virus (HCV) also remains a major medical problem, with 160 million chronically infected patients worldwide and only expensive treatments available. Despite distinct differences in their pathogenesis and modes of transmission, the two viruses share common replication strategies. A detailed understanding of the host functions that determine viral infection is lacking. Here we use a pooled CRISPR genetic screening strategy to comprehensively dissect host factors required for these two highly important Flaviviridae members. For DENV, we identified endoplasmic-reticulum (ER)-associated multi-protein complexes involved in signal sequence recognition, N-linked glycosylation and ER-associated degradation. DENV replication was nearly completely abrogated in cells deficient in the oligosaccharyltransferase (OST) complex. Mechanistic studies pinpointed viral RNA replication and not entry or translation as the crucial step requiring the OST complex. Moreover, we show that viral non-structural proteins bind to the OST complex. The identified ER-associated protein complexes were also important for infection by other mosquito-borne flaviviruses including Zika virus, an emerging pathogen causing severe birth defects. By contrast, the most significant genes identified in the HCV screen were distinct and included viral receptors, RNA-binding proteins and enzymes involved in metabolism. We found an unexpected link between intracellular flavin adenine dinucleotide (FAD) levels and HCV replication. This study shows notable divergence in host-depenency factors between DENV and HCV, and illuminates new host targets for antiviral therapy.

Dataset Information

Iminosugars: A host-targeted approach to combat Flaviviridae infections.

Publications

Iminosugars: A host-targeted approach to combat Flaviviridae infections.

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