Glucosylceramide synthase maintains influenza virus entry and infection

Drews, Kelly; Calgi, Michael P.; Harrison, William Casey; Drews, Camille M.; Costa-Pinheiro, Pedro; Shaw, Jeremy J.P.; Jobe, Kendra A.; Han, John D.; Fox, Todd E.; White, Judith M.

doi:10.1371/journal.pone.0228735

Cited by 24 publications

(27 citation statements)

References 53 publications

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“…In this study we demonstrate that the GCS inhibitors GZ-161 and GZ-346 have a broad spectrum Previous works showed that knocking out UGCG (the gene encoding for GCS) impaired the entry of Influenza virus by endocytosis (43). In addition to its role in endocytosis, the cellular membrane has a major role in establishing specialized membrane replication compartments (RCs) that are critical sites for the synthesis of the viral genome (44).…”

Section: Discussionmentioning

confidence: 68%

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Vitner

Avraham

Achdout

et al. 2020

Preprint

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One Sentence Summary: An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2. AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic.Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target.We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 68%

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Vitner

Avraham

Achdout

et al. 2020

Preprint

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“…It was recently shown that Ugcg knockout cells demonstrate a reduction in the replication of the respiratory RNA virus Influenza A virus, a member of the family Orthomyxoviridae ( 22 ). Thus, we further examined the antiviral activity of GCS inhibitors against Influenza A virus.…”

Section: Resultsmentioning

confidence: 99%

“…In this study we demonstrate that the GCS inhibitors GZ-161 and GZ-346 inhibit viral replication of SARS-CoV-2. The importance of glycosphingolipids biosynthesis in viral life cycle was demonstrated recently for Influenza virus and severe fever with thrombocytopenia syndrome virus (SFTSV) ( 22 , 23 ). Moreover, iminosugars are known for their broad-spectrum antiviral activity, presumably due to their mechanism of action as endoplasmic reticulum (ER)-resident α-glucosidases I and II inhibitors ( 24 ).…”

Section: Discussionmentioning

confidence: 96%

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Glucosylceramide synthase inhibitors prevent replication of SARS-CoV-2 and influenza virus

Vitner¹,

Achdout²,

Avraham³

et al. 2021

Journal of Biological Chemistry

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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 lifecycle, 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 FDA-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.

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“…Influenza virus induces GlcCer elevation [40,41] (Fig. 1), which seems to be important for viral life cycle since the suppression of the SL biosynthesis pathway results in the inhibition of the maturation of influenza virus particles [42][43][44]. In addition, ceramide glucosyltransferase (UGCG, GlcCer synthase) inhibitors have a broad antiviral activity against RNA viruses of different genus: neuroinvasive Sindbis virus (SVNI), West Nile virus (WNV), influenza A virus, and SARS-CoV-2.…”

Section: Associated Infectious Diseasesmentioning

confidence: 99%

The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

Vitner

2020

FEBS Letters

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Sphingolipidoses are diseases caused by mutations in genes responsible for sphingolipid degradation and thereby lead to sphingolipid accumulation. Most sphingolipidoses have a neurodegenerative manifestation characterized by innate immune activation in the brain. However, the role of the immune response in disease progression is ill-understood. In contrast to infectious diseases, immune activation is unable to eliminate the offending agent in sphingolipidoses resulting in ineffective, chronic inflammation. This paradox begs two fundamental questions: Why has this immune response evolved in sphingolipidoses? What role does it play in disease progression? Here, starting from the observation that sphingolipids (SLs) are elevated also in infectious diseases, I discuss the possibility that the activation of the brain immune response by SLs has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.

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Glucosylceramide synthase maintains influenza virus entry and infection

Cited by 24 publications

References 53 publications

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Glucosylceramide synthase inhibitors prevent replication of SARS-CoV-2 and influenza virus

The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

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