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

Abstract

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.

Gaucher disease and SARS-CoV-2 infection: Experience from 181 patients in New York

“…Our cohort included 40 adults taking eliglustat, a glucosylceramide synthase inhibitor, as SRT. Glucosylceramide synthase inhibitors were suggested to provide a protective effect by a previous report of an in vitro study [ 25 ], however we did not find our patients on eliglustat reported fewer symptoms or had a decreased probability of testing positive compared to those on ERT. Finally, we are reassured to find that GD with its chronic metabolic inflammatory state does not seem to be associated with severe outcomes of SARS-CoV-2 infection.…”

Effect of various treatment modalities on the novel coronavirus (nCOV-2019) infection in humans: a systematic review & meta-analysis

“…There were 32 preprints and 12 published articles amongst the selected studies. Fifteen studies were included from China(17-31), six from United States of America (USA) (32-37), five from France(38-42), four from Japan(43-46), two each from Germany(47,48), Netherlands(49,50) and South Korea(51,52) and one each from Australia(53), Brazil(54), Canada(55), Israel(56), Italy(57), Norway(58), Switzerland(59) and the United Kingdom (UK) (60).…”

“…One study each involving 47D11 H2L2 antibody, Arbidol(17), Atazanavir(54), Auranofin(32), Baicalein(18), Beta-d-N4-hydroxycytidine(33), Boceprevir(34), Darunavir(47), Genz-123346 (GlucosylCeramide synthase inhibitor)(56), Antibodies n3086/n3113(20), Interferon-α/ Interferon −(β(35), Indomethacin(24), Lianhuaqingwen(25), Miglustat(57), Naproxen(40), Pudilan Xiaoyan Oral Liquid(29), Suramin(50) and T-705 (Favipiravir)(42) had a wide range of EC 50 [0.15−207 μM] or IC50 [0.08−411.2μM] values. However, each of these compounds demonstrated the potential to stall the process of viral replication and growth through inhibiting viral titre in cell lines.…”

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

“…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. This suggests a key role of the glycosphingolipid synthesis pathway in viral infection [45]. The importance of GlcCer was also recognized as a universal target for combating fungi [46].…”