A systems‐level study reveals host‐targeted repurposable drugs against SARS‐CoV‐2 infection

Chen, Fangyuan; Shi, Qingya; Pei, Fen; Vogt, Andreas; Porritt, Rebecca A.; García, Gustavo; Gómez, Alejandro Raúl Gratacós; Cheng, Mary Hongying; Schurdak, Mark E.; Liu, Bing; Chan, Stephen Y.; Arumugaswami, Vaithilingaraja; Stern, Andrew M.; Taylor, D. Lansing; Arditi, Moshe; Bahar, İvet

doi:10.15252/msb.202110239

Cited by 30 publications

(18 citation statements)

References 124 publications

(156 reference statements)

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“…While most of the related works rely on the “signature reversal” hypothesis, in case of infection diseases, like COVID-19, it is less clear whether signature reversal (inhibiting the virus-hijacked signalisation) or signature similarity (promoting the antiviral response of infected host cells) can be more effective. While early studies at the beginning of the COVID-19 pandemic applied mostly the original signature reversal hypothesis, more recent works [ 52 , 53 ] also assumed that drugs with similarity to the SARS-CoV-2-induced gene expression signature can be effective. In our work, we performed a more unbiased analysis of signature-based drug repurposing against SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

et al. 2022

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Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity—and not inverse similarity—between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

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Section: Discussionmentioning

confidence: 99%

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

et al. 2022

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“…SARS-CoV-2 antibody-mediated serious inflammation results in bad consequence after COVID-19 infection [ 89 ]. Interestingly, 4HR shows some therapeutic effect on COVID-19 infection [ 90 ]. Detailed mechanism is unclear.…”

Section: Main Textmentioning

confidence: 99%

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

Kim

2022

Maxillofac Plast Reconstr Surg

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Abstract4-Hexylresorcinol (4HR) is amphiphilic organic chemical and auto-regulator for micro-organism. As 4HR administration induces the stress on the endoplasmic reticulum, 4HR changes protein folding. The application of 4HR inhibits NF-κB signal pathway and TNF-α production. In addition, 4HR administration increases VEGF, TGF-β1, and calcification associated proteins. As a consequence, 4HR administration increases angiogenesis and bone formation in wounded area. Strong anti-inflammatory reaction and capillary regeneration in diabetic model demonstrate that 4HR can be applied on many types of surgical wound.

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“…This approach enabled the identification of several kinase inhibitors that were antiviral without being cytotoxic (# 6, 8, 19, 22, 23, 29, 36, 38, 139, 148, 150, see Table S1 for designation) (Figure 1 and Supplementary Figure S1). Among them, we found inhibitors that are already proposed to negatively affect the SARS-CoV-2 life cycle (# 8, 22, 29, 38, 139) and/or to target kinases or even kinase signaling pathways already known to be utilized by SARS-CoV-2, namely receptor tyrosine kinases (# 22, 148), GSK3 (# 29), and components of the mTOR pathway (# 8, 19, 36) [51][52][53][54][55][56][57][58]. In addition, inhibitor # 23 (SB431542) reduced infection to 65% in comparison to the untreated infection control.…”

Section: Identification Of An Alk5 Kinase Inhibitor That Supresses Sa...mentioning

confidence: 99%

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

Mezger¹,

Conzelmann

Maltitz

et al. 2022

Viruses

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Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.

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A systems‐level study reveals host‐targeted repurposable drugs against SARS‐CoV‐2 infection

Cited by 30 publications

References 124 publications

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

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