T-type calcium channels blockers inhibit HSV-2 infection at the late stage of genome replication

Ding, Liqiong; Jiang, Ping; Xu, Xinfeng; Lu, Wanzhen; Yang, Chan; Lin, Li; Zhou, Pingzheng; Liu, Shuwen

doi:10.1016/j.ejphar.2020.173782

Cited by 17 publications

(12 citation statements)

References 23 publications

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“…Voltage-gated calcium channel activity is known to be involved in cell viral infection. In Vero cells, the application of T-type Ca 2+ channel selective blockers inhibited infection by Herpes simplex virus type 2 (HSV-2), which did not occur for voltage-gated L-type Ca 2+ channels. , Inhibition of T-type Ca 2+ channel activity by NNC 55-0396 did not affect membrane potential at most NaCl concentrations, indicating that this voltage-gated channel is not involved in the depolarization observed in Vero and Calu-3 cells (Figure a and b). Since there are several other types of voltage-gated Ca 2+ channels, we sought to evaluate if NaCl-induced depolarization promoted calcium transients in Vero cells in the first place (Figure c).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Machado

Glaser

Araújo

et al. 2021

ACS Pharmacol. Transl. Sci.

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An unprecedented global health crisis has been caused by a new virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We performed experiments to test if a hypertonic saline solution was capable of inhibiting virus replication. Our data show that 1.2% NaCl inhibited virus replication by 90%, achieving 100% of inhibition at 1.5% in the nonhuman primate kidney cell line Vero, and 1.1% of NaCl was sufficient to inhibit the virus replication by 88% in human epithelial lung cell line Calu-3. Furthermore, our results indicate that the inhibition is due to an intracellular mechanism and not to the dissociation of the spike SARS-CoV-2 protein and its human receptor. NaCl depolarizes the plasma membrane causing a low energy state (high ADP/ATP concentration ratio) without impairing mitochondrial function, supposedly associated with the inhibition of the SARS-CoV-2 life cycle. Membrane depolarization and intracellular energy deprivation are possible mechanisms by which the hypertonic saline solution efficiently prevents virus replication in vitro assays.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Machado

Glaser

Araújo

et al. 2021

ACS Pharmacol. Transl. Sci.

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“…Accordingly, ion channels have emerged as druggable host targets to prevent both RNA and DNA viruses from the successful completion of their life cycles. Given the known dependence of KSHV lytic replication on Ca 2+ signalling 20 , coupled to previous studies demonstrating the ability of VZV and HSV-1 to activate Na + and Ca 2+ family members 25,26 , we specifically investigated the role of B cell expressed ion channels during KSHV lytic reactivation. Using known pharmacological ion channel modulators, genetic silencing approaches and electrophysiological analysis, we reveal for the first time that KSHV requires a B-cell expressed voltage-gated K + channel, Kv1.3, to enhance lytic replication.…”

Section: Discussionmentioning

confidence: 99%

“…A catalogue of ion channel-blocking drugs have also been shown to possess antiviral activity, some of which are in widespread human use for ion channel-related diseases, highlighting new potential for drug repurposing. Amongst herpesviruses, varicella-zoster virus and herpes simplex virus have been shown to activate voltagegated Na + channels and voltage-gated Ca 2+ channels 25,26 . However, a specific role for host cell ion channels during the lytic replication stage of KSHV or any herpesvirus have yet to be fully defined.…”

Section: Introductionmentioning

confidence: 99%

K_v1.3 induced hyperpolarisation and Ca_v3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication

Carden

Dallas

Hughes

et al. 2021

Preprint

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Understanding the host factors critical for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication can identify new targets for therapeutic intervention. Using pharmacological and genetic silencing approaches, we reveal for the first time that KSHV requires a B cell expressed voltage-gated K+ channel, Kv1.3, to enhance lytic replication. We show that the KSHV replication and transcription activator (RTA) protein upregulates Kv1.3 expression, leading to enhanced K+ channel activity and hyperpolarisation of the B cell membrane. Enhanced Kv1.3 activity then promotes intracellular Ca2+ influx through Cav3.2, a T-type Ca2+ channel, leading to the Ca2+ driven nuclear localisation of NFAT and the subsequent NFAT1-responsive gene expression. Importantly, KSHV lytic replication and infectious virion production could be inhibited by both Kv1.3 and Cav3.2 blockers or through Kv1.3 silencing. These findings provide new mechanistic insight into the essential role of host ion channels during KSHV infection and highlight Kv1.3 and Cav3.2 as new druggable host factors that are key to the successful completion of KSHV lytic replication.

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“…Regarding which viruses the interventions were tested on, 113 (82.48%) studies used HSV-1 [ 1 - 3 , 6 - 16 , 19 , 21 - 27 , 29 - 31 , 33 - 35 , 37 , 38 , 40 - 44 , 46 - 49 , 51 , 53 - 56 , 60 - 65 , 67 - 74 , 76 - 79 , 82 , 83 , 85 - 99 , 103 - 123 , 125 - 134 , 136 - 138 ], 61 (44.53%) studies used HSV-2 [ 7 - 11 , 14 - 20 , 25 , 27 , 28 , 30 - 33 , 35 - 37 , 39 , 44 - 53 , 55 , 58 , 59 , 61 , 66 , 69 , 73 , 75 , 81 , 83 , 85 , 89 , 91 , 93 , 100 , 102 , 104 , 105 , 108 - 110 , 118 , ...…”

Section: Reviewmentioning

confidence: 99%

A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV

Lince¹,

DeMario²,

Yang³

et al. 2023

Cureus

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Drug-resistant variants of herpes simplex viruses (HSV) have been reported that are not effectively treated with first-line antiviral agents. The objective of this study was to evaluate available literature on the possible efficacy of second-line treatments in HSV and the use of second-line treatments in HSV strains that are resistant to first-line treatments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a final search was conducted in six databases on November 5, 2021 for all relevant literature using terms related to antiviral resistance, herpes, and HSV. Eligible manuscripts were required to report the presence of an existing or proposed second-line treatment for HSV-1, HSV-2, or varicella zoster virus (VZV); have full-text English-language access; and potentially reduce the rate of antiviral resistance. Following screening, 137 articles were included in qualitative synthesis. Of the included studies, articles that examined the relationship between viral resistance to first-line treatments and potential second-line treatments in HSV were included. The Cochrane risk-of-bias tool for randomized trials was used to assess risk of bias. Due to the heterogeneity of study designs, a meta-analysis of the studies was not performed. The dates in which accepted studies were published spanned from 2015-2021. In terms of sample characteristics, the majority (72.26%) of studies used Vero cells. When looking at the viruses on which the interventions were tested, the majority (84.67%) used HSV-1, with (34.31%) of these studies reporting testing on resistant HSV strains. Regarding the effectiveness of the proposed interventions, 91.97% were effective as potential managements for resistant strains of HSV. Of the papers reviewed, nectin in 2.19% of the reviews had efficacy as a second-line treatments in HSV, amenamevir in 2.19%, methanol extract in 2.19%, monoclonal antibodies in 1.46%, arbidol in 1.46%, siRNA swarms in 1.46%, Cucumis melo sulfated pectin in 1.46%, and components from Olea europeae in 1.46%. In addition to this griffithsin in 1.46% was effective, Morus alba L. in 1.46%, using nucleosides in 1.46%, botryosphaeran in 1.46%, monoterpenes in 1.46%, almond skin extracts in 1.46%, bortezomib in 1.46%, flavonoid compounds in 1.46%, andessential oils were effective in 1.46%, but not effective in 0.73%. The available literature reviewed consistently supports the existence and potentiality of second-line treatments for HSV strains that are resistant to first-line treatments. Immunocompromised patients have been noted to be the population most often affected by drug-resistant variants of HSV. Subsequently, we found that HSV infections in this patient population are challenging to manage clinically effectively. The goal of this systematic review is to provide additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments, especially those who are immunocompromised. All patients,...

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T-type calcium channels blockers inhibit HSV-2 infection at the late stage of genome replication

Cited by 17 publications

References 23 publications

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

K_v1.3 induced hyperpolarisation and Ca_v3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication

A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV

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T-type calcium channels blockers inhibit HSV-2 infection at the late stage of genome replication

Cited by 17 publications

References 23 publications

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 Replication by Hypertonic Saline Solution in Lung and Kidney Epithelial Cells

Kv1.3 induced hyperpolarisation and Cav3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication

A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV

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Product

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K_v1.3 induced hyperpolarisation and Ca_v3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication