Cellular protein GLTSCR2: A valuable target for the development of broad-spectrum antivirals

Li, Cuicui; Dong, Hui-Jun; Wang, Peng; Meng, Wen; Chi, Xiaojing; Han, Shuang; Ning, Shuo; Wang, Chuang; Wang, Xiao-Jia

doi:10.1016/j.antiviral.2017.03.004

Cited by 10 publications

(12 citation statements)

References 56 publications

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“…For each inoculation, a mixture of HHT (Aladdin, 98% purity) and NDV (50 plaque-forming units (PFU)) or AIV (500 PFU) was injected into the allantoic cavity of specific pathogen-free (SPF) chicken eggs. Eggs were incubated for different times, and allantoic fluid was harvested to measure viral yields, as described in our previous report [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

Dong

Wang

Meng

et al. 2018

Viruses

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To complement traditional antivirals, natural compounds that act via host targets and present high barriers to resistance are of increasing interest. In the work reported here, we detected that homoharringtonine (HHT) presents effective antiviral activity. HHT completely inhibited infections of vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and porcine epidemic diarrhea virus (PEDV) at concentrations of 50, 100, and 500 nM in cell cultures, respectively. Treatment with HHT at doses of 0.05 or 0.2 mg/kg significantly reduced viral load and relieved severe symptoms in PEDV- or NDV-infected animals. HHT treatment, however, moderately inhibited avian influenza virus (AIV) infection, suggesting its potent antiviral action is restricted to a number of classes of RNA viruses. In this study, we also observed that HHT actively inhibited herpes simplex virus type 1 (HSV-1) replication with a 50% inhibitory concentration (IC50) of 139 nM; the treatment with HHT at 1000 nM led to reductions of three orders of magnitude. Moreover, HHT antagonized the phosphorylation level of endogenous and exogenous eukaryotic initiation factor 4E (p-eIF4E), which might regulate the selective translation of specific messenger RNA (mRNA). HHT provides a starting point for further progress toward the clinical development of broad-spectrum antivirals.

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Section: Methodsmentioning

confidence: 99%

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

Dong

Wang

Meng

et al. 2018

Viruses

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“…Our previous study revealed that NOP53-derived recombinant protein N4-T, forming α-helical dimer, promotes replication of seven different viruses via suppression of the IFN-β antiviral response 44 . In consideration of the relationship between NOP53 redistribution and viral replication priority, N4-T protein was employed in this study.…”

Section: Nop53-derived Recombinant Protein Attenuates P-eif2α In Cellmentioning

confidence: 99%

“…N4-T, in which Tat (GGSRYGRKKRRQRRR) was conjugated at the C-terminal of N4, was expressed and purified as described previously 44 . Cells treated with N4-T were harvested for plaque formation assay or Western blotting analysis.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Meng

Han

et al. 2018

Cell Death Dis

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To ensure efficient virus replication, herpes simplex virus type 1 (HSV-1) encodes several viral proteins to counter host defense response upon infection. Among these proteins, the multifunctional viral protein γ34.5 crucially interferes with or disrupts several antiviral pathways at multiple levels. The current study shows that γ34.5 utilizes nucleolar protein NOP53 to facilitate the dephosphorylation of eukaryotic initiation factor eIF2α for efficient viral translation. Our study shows that: (1) ectopic expression of NOP53 greatly increases the intracellular and extracellular viral yields of HSV-1 (wild strain F) in type I interferon-deficient Vero cells, and more subtly promotes viral replication of γ34.5 deletion mutant virus HSV-1/Δγ34.5. (2) NOP53 is migrated from nuclei in HSV-1/F infected cells, but is redistributed incompletely after infection by either HSV-1/Δγ34.5 or ICP4 deletion mutant virus HSV-1/d120 (replication inadequate). Ectopic expression of γ34.5, consequently, induces cytoplasmic translocation of NOP53 in response to HSV-1/Δγ34.5 infection. (3) Increase of NOP53, in two forms of transient transfection and in vitro expression, attenuates the phosphorylation level of eIF2α in HSV-1/F infected cells, but fails to affect eIF2α phosphorylation induced by HSV-1/Δγ34.5 infection. (4) Knockdown of NOP53, which impairs the specific interaction between γ34.5 and protein phosphatase PP1α, disrupts the ability of γ34.5 to maintain HSV-1 virulence. (5) NOP53 knockdown also significantly reduces tissue damage and decreases viral yield in livers of HSV-1 infected mice. Our findings expand the understanding of the underlying mechanism by which viral protein γ34.5 induces NOP53 redistribution; cytoplasmic NOP53 facilitates γ34.5 recruitment of PP1α to dephosphorylate eIF2α, for optimal viral replication. This paper also demonstrates that blocking the specific interaction between γ34.5 and PP1α would be a useful approach for the development of antiviral agents.

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“…In RNA interference (RNAi), short interfering RNA molecules or short hairpin RNA (shRNA) targeting speci c mRNA leads to degradation of mRNA and inhibition of gene expression [6][7]. RNAi targeting viral genes is an effective way to prevent cells from virus infection, and has been shown to mediate genetic suppression of many human and animal pathogenic coronaviruses [8,9,10]. Heptad repeat (HR) regions are highly conserved motifs located in spike glycoprotein of enveloped viruses.…”

Section: Introductionmentioning

confidence: 99%

Three kinds of treatment with Homoharringtonine, Hydroxychloroquine or shRNA and their combination against coronavirus PEDV in intro

Wang²

2020

Preprint

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Background: Porcine epidemic diarrhea virus (PEDV) of the family Coronaviridae has caused substantial economic losses in the swine husbandry industry. There’s currently no specific drug available for treatment of coronaviruses or PEDV. Method: In the current study, we use coronavirus PEDV as a model to study antiviral agents. Briefly, a fusion inhibitor tHR2, recombinant lentivirus-delivered shRNAs targeted to conserved M and N sequences, homoharringtonine (HHT), and hydroxychloroquine (HCQ) were surveyed for their antiviral effects. Results: Treatment with HCQ at 50 mM and HHT at 150 nM reduced virus titer in TCID50 by 30 and 3.5 fold respectively, and the combination reduced virus titer in TCID50 by 200 fold. Conclusion: Our report demonstrates that the combination of HHT and HCQ exhibited higher antiviral activity than either HHT or HCQ exhibited. The information may contribute to the development of antiviral strategies effective in controlling PEDV infection.

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Cellular protein GLTSCR2: A valuable target for the development of broad-spectrum antivirals

Cited by 10 publications

References 56 publications

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Three kinds of treatment with Homoharringtonine, Hydroxychloroquine or shRNA and their combination against coronavirus PEDV in intro

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