Inhibition of herpes simplex virus 1 by cepharanthine via promoting cellular autophagy through up-regulation of STING/TBK1/P62 pathway

Liu, Yao; Tang, Qiong; Rao, Zhili; Yang, Fang; Jiang, Xinni; Chen, Li; Luan, Fei; Zeng, Nan

doi:10.1016/j.antiviral.2021.105143

Cited by 30 publications

(33 citation statements)

References 52 publications

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“…Our previous experiments confirm that CEP has no obvious cytotoxicity under 3 μg/mL concentration. The median toxic concentration (TC 50 ) is 5.4 μg/mL, the median inhibitory concentration (IC 50 ) is 0.835 μg/mL, and the therapeutic index (TI) of CEP is 6.47 ( Liu et al, 2021 ). In this study, Vero cells were infected with HSV-1 (MOI = 1) for 2 h and treated with CEP (3, 1.5, and 0.75 μg/mL).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, CEP could be considered as a potential therapeutic antiviral drug of interest for treating HSV-1. Our recent study shows that CEP has a significant adverse influence on HSV-1 infection in vitro , whereas the underlying mechanism is only preliminarily explored ( Liu et al, 2021 ). To further correlate the antiviral applications of CEP with its underlying molecular mechanisms, the anti-HSV-1 effects, and mechanisms of CEP are explored in vitro in this study.…”

Section: Introductionmentioning

confidence: 99%

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Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways

et al. 2021

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Cepharanthine (CEP) is a naturally occurring isoquinoline alkaloid extracted from Stephania cepharantha Hayata. Although its underlying molecular mechanism is not fully understood, this compound is reported as a promising antiviral drug. In the present study, we explore the anti-HSV-1 effects and the underlying molecular mechanisms of CEP in vitro. Our results show that CEP could significantly inhibit the formation of plaque and the expression of viral proteins and exhibit a general suppression of replication-associated genes. Whereas HSV-1 infection increases the expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38 MAPK) in host cells, CEP was effective indirectly inhibiting phosphorylation levels of the targets in PI3K/Akt and p38 MAPK signaling pathways. Moreover, CEP markedly decreased G0/G1 phase and increased G2/M phase cells and decreased the expression of cyclin-dependent kinase1 (CDK1) and cyclinB1 in a dose-dependent manner. Additionally, CEP increased apoptosis in infected cells, reduced B cell lymphoma-2 (Bcl-2) protein levels, and increased the protein levels of Bcl-associated X protein (Bax), cleaved-caspase3, and nuclear IκB kinaseα (IκBα). Collectively, CEP could arrest the cell cycle in the G2/M phase and induce apoptosis in infected cells by inhibiting the PI3K/Akt and p38 MAPK signaling pathways, hence further reducing HSV-1 infection and subsequent reproduction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways

et al. 2021

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“…AC#7 was originally derived from glycyrrhiza glabra, which has been found to have versatile bioactivity, including antiviral activity [ 70 , 71 , 72 , 73 ]. This molecule contains benzofuran and isoquinoline elements ( Figure 2 ), which have both been found to possess antiviral abilities [ 74 , 75 , 76 ]. To the best of our knowledge, this is the first report of antiherpetic activity of a molecule with both benzofuran and isoquinoline elements in vitro, suggesting a promising foundation for designing a new generation of antiviral drugs via medicinal chemistry.…”

Section: Discussionmentioning

confidence: 99%

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D

Power

Miranda-Saksena

et al. 2022

Pharmaceuticals

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Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.

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“…Autophagy acts as an antiviral mechanism that can inhibit infection by packaging viruses in the autophagosome ( Liang et al., 1998 ; Liu et al., 2005 ), whereas many pathogens utilize autophagy for their replication ( Dreux and Chisari, 2010 ). Some viruses, such as herpes simplex virus type 1 (HSV-1) ( Orvedahl et al., 2007 ; Liu et al., 2021 ) and human cytomegalovirus (HCMV) ( Chaumorcel et al., 2008 ) have evolved different strategies to disrupt the process of autophagy for their survival. However, viruses can also functionally utilize autophagy to ensure their own infection, especially for RNA viruses, such as porcine reproductive and respiratory syndrome virus (PRRSV) ( Sun et al., 2012 ), coxsackievirus B3 ( Wong et al., 2008 ), and Newcastle disease virus (NDV) ( Sun et al., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Porcine Epidemic Diarrhea Virus by Cinchonine via Inducing Cellular Autophagy

Ren

Zeng

Jiang

et al. 2022

Front. Cell. Infect. Microbiol.

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Porcine epidemic diarrhea virus (PEDV) could cause lethal diarrhea and dehydration in suckling piglets, which can adversely affect the development of the global swine industry. The lack of effective therapeutical and prophylactic treatment especially for PEDV variant strains underlines the importance of effective antiviral strategies, such as identification of novel antiviral agents. In the present study, the antiviral activity of cinchonine against PEDV was investigated in Vero CCL81 and LLC-PK1 cells at a non-cytotoxic concentration determined by Cell Counting Kit-8 assay in vitro. We found that cinchonine exhibited a significant suppression effect against PEDV infection and its inhibitory action was primarily focused on the early stage of PEDV replication. Moreover, we also observed that cinchonine could significantly induce autophagy by detecting the conversion of LC3-I to LC3-II by using western blot analysis. Cinchonine treatment could inhibit PEDV replication in a dose-dependent manner in Vero CCL81 cells, while this phenomenon disappeared when autophagy was attenuated by pre-treatment with autophagy inhibitor 3MA. Consequently, this study indicated that cinchonine can inhibit PEDV replication via inducing cellular autophagy and thus from the basis for successful antiviral strategies which potentially suggest the possibility of exploiting cinchonine as a novel antiviral agent.

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Inhibition of herpes simplex virus 1 by cepharanthine via promoting cellular autophagy through up-regulation of STING/TBK1/P62 pathway

Cited by 30 publications

References 52 publications

Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways

Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D

Inhibition of Porcine Epidemic Diarrhea Virus by Cinchonine via Inducing Cellular Autophagy

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