Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro

Abstract

Zika virus (ZIKV), a vector-borne virus of the family Flaviviridae, continues to spread and remains a significant global public health threat. Currently, there are no approved vaccines or antivirals against ZIKV. We investigated the anti-ZIKV ability of three iminosugars with endoplasmic reticulum α-glucosidase inhibitor (ER-AGI) activity, namely deoxynojirimycin (DNJ), castanospermine, and celgosivir. None of the three iminosugars showed any significant cytotoxicity in Vero or human microglia CHME3 cells when applied for 72 h at concentrations up to 100 µM. Iminosugar treatment of Vero or CHME3 cells prior to ZIKV infection resulted in significant inhibition of ZIKV replication over 48 h. Reduction in ZIKV replication in iminosugar-treated cells was not associated with any significant change in the expression levels of key antiviral genes. Following infection with three different strains of ZIKV, iminosugar-treated Vero or CHME3 cells showed no cell death, whereas vehicle-treated control cells exhibited 50-60% cell death at 72 h post-infection (hpi). While there was no significant difference in apoptosis between iminosugar-treated and control cells, iminosugar-treated cells exhibited a substantial reduction of necrosis at 72 hpi following ZIKV infection. In summary, iminosugars with ER-AGI activity inhibit ZIKV replication and significantly reduce necrosis without altering the antiviral gene expression and apoptosis of infected human cells. The results of this study strongly suggest that iminosugars are promising anti-ZIKV antiviral agents and such warrant further in vivo studies.

A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19

“…The importance of protein glycosylation is evidenced by the use of Celgosivir (an inhibitor of N-glycan synthesis) in treating cells that harbour Dengue virus, which prevents proper protein glycosylation, leading to protein misfolding and impaired replicative e ciency (17). Celgosivir (and also other iminosugars such as deoxynojirimycin or castanospermine) has been shown to be a very promising drug, not only for the treatment of Dengue virus or members of the same family (like for example ZIKV), but also for other viruses belonging to different families, such as the hepatitis C or In uenza viruses (18)(19)(20). As 3 of our 10 selected enzyme targets are involved in the N-Glycan biosynthesis pathway (i.e.…”

Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives

“…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 ). The iminosugars deoxynojirimycin, castanospermine, and celgosivir tested against ZIKV in vitro were able to reduce viral RNA and infectious virus titers in Vero and CHME3 cells with no effect on cellular apoptosis and antiviral responses ( 213 ). To increase their efficacy against EBOV and YFV infections, Ma et al ( 214 ) proposed to use them in association with other antiviral molecules.…”

Natural Products Database Screening for the Discovery of Naturally Occurring SARS‐Cov‐2 Spike Glycoprotein Blockers

“…These biological effects were clearly evident after administration with Castanospermine in the prevention of death in mice infected with flaviviruses and filoviruses, in the suppression of virus multiplication in other infected animals, and in clinical trials against human immunodeficiency, hepatitis C and B, human parainfluenza virus type 3 (HPIV3), Ebola, Zika, and dengue virus. [22][23][24][25][26] This compound seems to be a promising candidate among the large plethora of derivatives tested on SARS-CoV-2. [27]…”