Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication

Cheng, Mei‐Ling; Wu, Chien‐Hsiang; Chien, Kun-Yi; Lai, Chien-Hsueh; Li, Guan-Jie; Liu, Yuan-Yu; Lin, Gigin; Ho, Hung‐Yao

doi:10.3390/v14081717

Cited by 15 publications

(13 citation statements)

References 89 publications

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“…37 VDAC3 interaction was found to be associated with a reduction in the synthesis of hypotaurine, an important endogenous antioxidant that plays a role in maintaining the homoeostasis of ROS levels. 38 Fourth, VDAC can interact with or promote the activation of other proteins to reduce the apoptosis of infected cells. It was confirmed that VDAC2 promotes apoptosis of IBDV-infected cells when triggered by IBDV protein VP5 39 ; however, when receptor of activated protein C kinase 1 (RACK1) forms a complex with VP5 and VDAC2, apoptosis is inhibited.…”

Section: Vdac-dependent Mechanisms That Enhance Viral Infectionmentioning

confidence: 99%

“…32 Additionally, in an experiment on EV71-infected cells in which VDAC3 was knocked down, both titre and genomic RNA levels were significantly reduced. 38 Moreover, a study on LCDV infection and the possible role of the VDAC2/RACK1 complex in viral entry and replication revealed that knocking down the VDAC2/RACK1 complex resulted in lower LCDV copy numbers and viral load in LCDVinfected FG cells, shedding light on the importance of this complex to promote viral entry. 31 According to the study by Sheng and colleagues, viral entry was mediated by the caveolae-dependent endocytic pathway, which can potentially be targeted to prevent viral entry.…”

Section: Viral Infection Inhibition By Downregulation Of Vdacmentioning

confidence: 99%

“…39 Another study focusing on VDAC3 role in EV71 infection showed that treatment with the mitochondrial-specific antioxidant Mito-TEMPO (C 29 H 35 N 2 O 2 P.Cl) caused the EV71 RNA levels to decrease substantially. 38 In addition, arsenic trioxide (As 2 O 3 ) was used to upregulate VDAC in human myeloma cells, whereby high expression of VDAC was correlated with induced apoptosis of mouse uterine epithelial cells. 67,68 Because it was established that ROS generation is a common viral pathogenic mechanism, the host cells response T A B L E 3 Overview of the aforementioned drugs with their mechanism of action and targeted pathways.…”

Section: Potential Antiviral Drugs That Target Vdacmentioning

confidence: 99%

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Voltage‐dependent anion channels: Key players in viral infection

Saadawy,

Khalil,

Sidarous

et al. 2023

Reviews in Medical Virology

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Viruses control the host cell by exploiting its molecular machinery to facilitate viral replication and propagation. Understanding different viral mechanisms and biochemical pathways is crucial for finding promising therapeutic solutions to viral infections. The mitochondrion is a vital organelle targeted by various types of viruses. More specifically, viruses interact with the voltage‐dependent anion channel (VDAC), a porin protein found in the outer mitochondrial membrane. VDAC controls metabolite flux, regulates reactive oxygen species production, and promotes mitochondrial‐mediated apoptosis by releasing pro‐apoptotic proteins. Hence, a common pathogenic strategy used by many viruses seems to exploit natural pathways that VDAC regulates. This review aims to address the inhibition and enhancement roles of VDAC in viral pathogenesis and outlines multiple links and interactions between VDAC and viral proteins as potential antiviral targets.

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Section: Vdac-dependent Mechanisms That Enhance Viral Infectionmentioning

confidence: 99%

Section: Viral Infection Inhibition By Downregulation Of Vdacmentioning

confidence: 99%

Section: Potential Antiviral Drugs That Target Vdacmentioning

confidence: 99%

See 1 more Smart Citation

Voltage‐dependent anion channels: Key players in viral infection

Saadawy,

Khalil,

Sidarous

et al. 2023

Reviews in Medical Virology

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“…Superoxide anion production was determined by MitoSOX Red staining and flow cytometry as previously described [50]. The mitochondrial mass and mitochondrial membrane potential were determined, respectively, by staining with MitoTracker Green and JC-1 and performing cytometric analyses as previously described [51,52].…”

Section: Oxygen Consumption Rate (Ocr) and Extracellular Acidificatio...mentioning

confidence: 99%

Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation

Cheng

Yang

et al. 2023

IJMS

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The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of β-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd−/−) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.

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“…EV71 infection also leads to increased ROS generation, accompanied by decreased levels of antioxidants (taurine and hypotaurine) [9]. It was shown, that enteroviral 2B protein interacts with mitochondrial voltage-dependent anion channel 3 (VDAC3) -one of the pore-forming protein localized to the outer membrane of mitochondria, and this interaction is essential to mitochondrial ROS generation and viral replication [10]. It is described that oxidative stress elicited by viruses can promote inflammation and subsequent tissue destruction [30,19].…”

Section: Figure 7 1a Inhibits Early and Middle Stages Of Coxsackievir...mentioning

confidence: 99%

Antiviral properties of verdazyls and leucoverdazyls and their activity against group B enteroviruses

Волобуева

Zarubaev

Fedorchenko

et al. 2023

Russian Journal of Infection and Immunity

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Introduction: Enteroviruses are non-enveloped viruses of the Enterovirus genus of the Picornaviridae family. They cause human diseases ranging from respiratory diseases to more severe cases, including polio, encephalitis, myocarditis, and pancreatitis. To date, there are no approved direct-acting antiviral drugs for the treatment of enterovirus diseases, therefore search for new small molecules - inhibitors of the enterovirus life cycle is important. Objective: to characterize the antiviral properties of new stable free radicals, verdazyls, and their precursors, leucoverdazyls. Leucoverdazyls have previously been shown to have antioxidant potential. Materials and methods: leucoverdazyls and verdazyls were synthesized in the Laboratory of coordination compounds, Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, Russian Federation. The following strains and cell cultures were used: influenza A virus (strain A/Puerto Rico/8/1934 H1N1), Coxsackie virus B3 (CVB3, Nancy strain), Coxsackie virus B4 (CVB4, Powers strain), Coxsackie virus B5, herpes simplex virus type 1 (HSV1) and human adenovirus 5 (Ad5) obtained from the collection of the Pasteur Research Institute (St. Petersburg). The following cell cultures were used: MDCK (ATCC #CCL-34), Vero (ATCC #CCL-81), A549 (ATCC #CCL-185). Infectious activity of viruses was assessed by end point titration. The cytoprotective activity and cytotoxicity of the compounds were evaluated using MTT test. The antiviral activity of the compounds was evaluated in the viral yield reduction assay. The virucidal activity of the compounds was evaluated after incubation of the compounds in a cell-free system with Coxsackie B4 virus for 1 hour. To investigate the mechanism of action of the leader compound, a time-of-addition assay was performed. Results: Leucoverdazyls, unlike verdazyls, have cytoprotective activity when a permissive culture is infected with the Coxsackie B3 virus. The leading compound was identified: 1a, which demonstrated a high inhibitory ability against a wide panel of influenza B enteroviruses in micromolar range (IC50=5.48 M and 0.72 M for Coxsackie B3 and Coxsackie B4, respectively) and its activity was superior to pleconaril (IC50=15.2 and IC50=1.91). Nevertheless, pleconaril acted as a more powerful inhibitor than 1a towards Coxsackievirus B5. The compound showed only slight activity against influenza A (RNA virus), no activity against Ad5 and HSV1 (DNA viruses). 1a have no virucidal activity. The maximum decrease in the titers of viral progeny with the addition of 1a was observed in the early and middle stages of the life cycle of the Coxsackie virus. Conclusion: Leucoverdazyls are potent inhibitors of group B enteroviruses in vitro. Leucoverdazyl 1a doesnt belong to capsid binder class of inhibitors and has no virucidal activity against coxsackievirus. Further studies are needed to elucidate their precise mechanisms of action including assessment of its direct impact on intracellular ROS generation, resistant clone selection and mapping of resistance mutations. We plan to expand the library of leucoverdazyls through targeted chemical modifications in order to disclose its pharmacophore and improve their virus-inhibiting properties. Nevertheless, the results of the study can serve as a basis for future development of novel antivirals to use in monotherapy or in combinational treatment of enteroviral infections.

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Enteroviral 2B Interacts with VDAC3 to Regulate Reactive Oxygen Species Generation That Is Essential to Viral Replication

Cited by 15 publications

References 89 publications

Voltage‐dependent anion channels: Key players in viral infection

Voltage‐dependent anion channels: Key players in viral infection

Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation

Antiviral properties of verdazyls and leucoverdazyls and their activity against group B enteroviruses

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