Iminosugars: A host-targeted approach to combat Flaviviridae infections

• Published in: Antiviral research 2020-12, Vol.184, p.104881-104881, Article 104881
• Main Authors: Evans DeWald, Lisa, Starr, Chloe, Butters, Terry, Treston, Anthony, Warfield, Kelly L.
• Format: Article
• Language: English
• Subjects: alpha-Glucosidases; Animals; Antiviral Agents - pharmacology; Antiviral therapy; ER α-glucosidases; Flaviviridae; Flaviviridae - drug effects; Flaviviridae - genetics; Flaviviridae Infections - drug therapy; Flavivirus; Glycoside Hydrolase Inhibitors; Glycosylation; Glycosylation - drug effects; Host Microbial Interactions; Humans; Imino Sugars - chemistry; Imino Sugars - pharmacology; Iminosugars; Invited Review; Mice; Viral Proteins - metabolism
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2020.104881

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 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. •Certain iminosugars can interfere with the N-inked glycosylation pathway, impacting host and viral protein glycosylation.•Iminosugars have demonstrated activity against multiple members of the Flaviviridae family in vitro and in murine models.•Multiple iminosugars are currently in preclinical development as broad-spectrum host-targeted antiviral therapies.•Targeting other Flaviviridae ER-associated host dependency factors may provide an additional approach for novel antivirals.