Abstract
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.
Highlights
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health
We examined the antiviral activity of two specific inhibitors of UDP-glucose:ceramide glucosyltransferase (glucosylceramide synthase (GCS)), (EC 2.4.1.80), which catalyze the biosynthesis of GlcCer
To test for antiviral activity of GCS inhibitors against SARS-CoV-2, Vero E6 cells were incubated with 10-μM GZ161 or GZ-346 1 h before infection with SARS-CoV-2
Summary
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Antiviral drugs which inhibit the replication of SARS-CoV-2 can be used widely to treat patients after infection. The antiviral activity of GCS inhibitors was examined for SARS-CoV-2.
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