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Review
. 2020 Dec:184:104881.
doi: 10.1016/j.antiviral.2020.104881. Epub 2020 Aug 5.

Iminosugars: A host-targeted approach to combat Flaviviridae infections

Lisa Evans DeWald  1 , Chloe Starr  1 , Terry Butters  2 , Anthony Treston  1 , Kelly L Warfield  3
Affiliations
Review

Iminosugars: A host-targeted approach to combat Flaviviridae infections

Lisa Evans DeWald et al. Antiviral Res. 2020 Dec.

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 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.

Keywords: Antiviral therapy; ER α-glucosidases; Flaviviridae; Flavivirus; Glycosylation; Iminosugars.

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Figures

Fig. 1
Fig. 1
Bicyclic iminosugars evaluated for activity against members of the Flaviviridae family. Structures for bicyclic iminosugars that have been tested for activity in vitro and in vivo against members of the Flaviviridae family, both of which have advanced to in clinical trials as potential HTAVs to combat Flaviviridae infections (Watanabe et al., 2012).
Fig. 2
Fig. 2
DNJ derivatives evaluated in vitro for activity against a single member of the Flaviviridae family. Structures for monocyclic glucose-mimicking iminosugars that have been tested for activity in vitro against a single virus in the Flaviviridae family (Kiappes et al., 2018).
Fig. 3
Fig. 3
DNJ derivatives evaluated in vitro for activity against multiple members of the Flaviviridae family. Structures for monocyclic glucose-mimicking iminosugars that have been tested for activity in vitro against two or more members of the Flaviviridae family (Schul et al., 2007).
Fig. 4
Fig. 4
DNJ derivatives evaluated in vitro and in vivo for activity against members of the Flaviviridae family. Structures for monocyclic glucose-mimicking iminosugars that have been tested for activity against Flaviviridae in vitro and in animal models of disease or that have advanced to clinical development for Flaviviridae infections.
Fig. 5
Fig. 5
DGJ and other non-glucose-mimicking iminosugars evaluated in vitro or in vivo for activity against members of the Flaviviridae family. Structures for iminosugars containing headgroups that mimic galactose (DGJ and DGJ-derivatives) or mannose (DMJ) that have been tested for activity against Flaviviridae in vitro or in animal models of disease.
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