Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

Zheng, Kai; Chen, Maoyun; Xiang, Yangfei; Ma, Kaiqi; Jin, Fujun; Wang, Xiao; Wang, Xiaoyan; Wang, Shaoxiang; Wang, Yifei

doi:10.1016/j.bbrc.2014.03.050

Cited by 39 publications

(33 citation statements)

References 28 publications

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“…4a). A similar trend has been reported for ACV 36 . To assess the main and temporally last viral step targeted by c-exNDI, we performed a time of addition (TOA) assay where the maximal low/mild-cytotoxic concentration of the compound was added at different times post-infection (corresponding to different viral cycle steps).…”

Section: Resultssupporting

confidence: 89%

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A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro

Perrone

Scalabrin

et al. 2017

Sci Rep

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G-quadruplexes (G4s) are nucleic acids secondary structures, epigenetic regulators in cells and viruses. In herpes simplex virus 1 (HSV-1)-infected cells, G4s are massively present during viral replication. We here aimed at investigating the possibility to target the HSV-1 G4s by a core extended naphtalene diimide (c-exNDI) G4 ligand. Biophysical and biomolecular analysis proved that c-exNDI stabilized the HSV-1 G4s in a concentration dependent manner. In MS competition assays, c-exNDI preferentially recognized HSV-1 G4s over cellular telomeric G4s, the most represented G4s within cells; other less abundant cellular G4s were also recognized. Treatment of HSV-1 infected cells with c-exNDI at low nanomolar concentrations induced significant virus inhibition with no cytotoxicity. The mechanism of action was ascribed to G4-mediated inhibition of viral DNA replication, with consequent impairment of viral genes transcription. Our data suggest that the observed potent antiviral activity and low cytotoxicity mainly depend on a combination of c-exNDI affinity for HSV-1 G4s and their massive presence during infection. HSV-1 G4s may thus represent new effective antiviral targets: the fact that no current antiherpetic drug exploits them and their presence at the viral genome, responsible for both active and latent HSV infections, makes them particularly attracting.

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Section: Resultssupporting

confidence: 89%

“…Impairment of viral replication led to the decrease of viral genes in all phases of the viral life cycle. This effect is shared between c-exNDI and ACV 36 . We have previously shown that the general G4 ligand, BRACO-19, mainly decreased L viral genes 27 .…”

Section: Discussionmentioning

confidence: 80%

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro

Perrone

Scalabrin

et al. 2017

Sci Rep

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“…More specifically, Cl À channel modulation was found to affect viral fusion processes by inhibiting viral protein binding to lipid rafts and interrupting Ca 2+ homeostasis [14]. Since tamoxifen is a clinically available drug (though not entirely specific for Cl À channels), future studies assessing its effect on HSV-1 infection in vivo may reveal intriguing insights into its therapeutic potential for this virus family.…”

Section: Hiv-1 Bkcamentioning

confidence: 99%

Viral dependence on cellular ion channels – an emerging anti-viral target?

Hover

Foster

Barr

et al. 2017

Journal of General Virology

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The broad range of cellular functions governed by ion channels represents an attractive target for viral manipulation. Indeed, modulation of host cell ion channel activity by viral proteins is being increasingly identified as an important virus-host interaction. Recent examples have demonstrated that virion entry, virus egress and the maintenance of a cellular environment conducive to virus persistence are, in part, dependent on virus manipulation of ion channel activity. Most excitingly, evidence has emerged that targeting ion channels pharmacologically can impede virus life cycles. Here, we discuss current examples of virus-ion channel interactions and the potential of targeting ion channel function as a new, pharmacologically safe and broad-ranging anti-viral therapeutic strategy.

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“…The selective estrogen receptor modulators (SERMs) toremifene (109) and clomiphene (110) were also reported to inhibited several other viruses such as HIV-1, 246 EBOV, 247 and HSV. 248 However, the mechanism studies have excluded ERα as potential antiviral targets, and the observed broad-spectrum antiviral property for SERMs resulted from the inhibition of other host factors, including protein kinase C (HIV-1) 249 and chloride channel (HSV-1). 248 These host proteins together with ERα represent promising targets for the development of novel antiviral agents to combat against drug resistance and newly emerging unknown viruses.…”

Section: Ns5b-estrogen Receptor α Interactionmentioning

confidence: 99%

Medicinal chemistry strategies toward host targeting antiviral agents

2020

Medicinal Research Reviews

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Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents

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Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

Cited by 39 publications

References 28 publications

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Viral dependence on cellular ion channels – an emerging anti-viral target?

Medicinal chemistry strategies toward host targeting antiviral agents

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