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.
【저자키워드】 COVID-19, SARS-CoV-2, antiviral drugs, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, breath, glucosylceramide, sphingolipids, glucosylceramide synthase, CC50, cytotoxicity concentration 50%, CPE, cytopathic effect, DENV, dengue virus, DMSO, dimethyl sulfoxide, DNJ, deoxynojirimycin, DsiRNA, Dicer-substrate siRNA, GCS, glucosylceramide synthase, GlcCer, glucosylceramide, GZ-161, GENZ-667161, GZ-346, Genz-123346, LSD, lysosomal storage disease, MDCK, Madin–Darby Canine Kidney, MOI, multiplicity of infection, NB-DNJ, N-butyl–DNJ, PR8, influenza virus A/PR/8/34 (H1N1), SI, selective index, 【초록키워드】 Treatment, viruses, Vaccine, coronavirus, Influenza, COVID-19 pandemic, Infection, clinical trials, Influenza virus, drug, severe acute respiratory syndrome Coronavirus, virus, Antiviral effect, global health, Replication, outcomes, Health, Viral, membrane, H1N1, cross, United States, glucosylceramide, respiratory, inhibitor, synthesis, food, therapeutic target, life cycle, not applicable, host cell, antiviral therapies, life cycles, specific inhibitors, venglustat, specific inhibitor, Support, dependency, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, host cell membrane, Drug administration, viral life cycle, component, cell membranes, host cell membranes, Phase III clinical trials, analogue, Cerdelga, replication of SARS-CoV-2, Prevent, limit, examined, caused, the United State, inhibit, disrupt, creating, 【제목키워드】 Influenza, inhibitor, replication of SARS-CoV-2, Prevent,