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 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 discuses 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 specific. 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.

Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens

“…In SARS-CoV-2 iminosugars have shown broad-spectrum antiviral activity in vivo and in vitro. 199 However, iminosugars are still to be approved for the treatment of viral infections and their potential use as host-targeted antiviral therapies is still to be investigated. Figure 4 provides a simplified presentation of N-Linked glycosylation pathway and Table 5 comprises a list of antivirals acting against glycosylation pathways.…”

Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives

“…Two families of α-glucosidase inhibitors, 1-deoxynojirimycin (DNJ)-derived (monocyclic) and indolizidine compounds (bicyclic, celgosivir/castanospermine, the active form), have been reported to be active in vitro against many enveloped viruses, including DENV, JEV, and ZIKV (IC 50 range, 40 nM to 20 μM, depending on the virus, the compound, and the cell type), EBOV and Marburg virus (IC 50 range, 6 to 33 and 8 to 48 μM for EBOV and Marburg virus, respectively, depending on the compound), and influenza virus. These compounds have also been shown to be active in vivo in animal models of DENV, JEV, EBOV, influenza virus, and Marburg virus (reviewed in reference 209 ; see also references 210 and 211 ). UV-4 iminosugar [ N -(9-methoxynonyl)-1-deoxynojirimycin] has been described to present a low risk for selection of drug-resistant influenza A (H1N1 and H3N2 subtypes) and B mutant viruses in vitro and in vivo ( 212 ).…”

Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus

“…This cytotoxic effect in HUH-7 cells and cytostatic effect in HFF-1 cells likely contributed to apparent UV-4B activity at high concentrations as viral replication is dependent on the presence of actively replicating cells. UV-4B has been investigated as a potential therapeutic option against DENV and influenza viruses [ 15 , 16 ]; however, its broad spectrum activity is likely to extend to other flaviviruses as these are also dependent on ER α-glucosidases for proper processing and folding of envelope glycoproteins [ 35 , 36 , 37 ]. This is an active are of investigation in our laboratory, as UV-4B holds promise as an antiviral candidate with broad spectrum activity against other flaviviruses including Zika and West Nile virus.…”