Assessing the potential of repurposing ion channel inhibitors to treat emerging viral diseases and the role of this host factor in virus replication

Russell, Tristan; Gangotia, Disha; Barry, Gerald

doi:10.1016/j.biopha.2022.113850

Cited by 5 publications

(2 citation statements)

References 286 publications

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“…TPC1, in contrast, is a voltage-dependent channel that is activated by PI (3,5) P 2 , the second messenger of NAADP, and changes in pH [ 41 - 45 ]. TPC2, although independently activated by voltage [ 40 , 42 , 46 ], has caused some problems regarding its activator. Some studies have suggested that TPC channels are activated by PI (3,5) P 2 and increase Na + influx [ 43 ], whereas others have proposed that NAADP activates Ca 2+ influx, which is associated with TFEB translocation [ 47 ].…”

Section: The Role Of Ion Channels In Maintaining Lysosomal Functionmentioning

confidence: 99%

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

Jung

Kim

Shin

et al. 2023

Korean J Physiol Pharmacol

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Ion homeostasis, which is regulated by ion channels, is crucial for intracellular signaling. These channels are involved in diverse signaling pathways, including cell proliferation, migration, and intracellular calcium dynamics. Consequently, ion channel dysfunction can lead to various diseases. In addition, these channels are present in the plasma membrane and intracellular organelles. However, our understanding of the function of intracellular organellar ion channels is limited. Recent advancements in electrophysiological techniques have enabled us to record ion channels within intracellular organelles and thus learn more about their functions. Autophagy is a vital process of intracellular protein degradation that facilitates the breakdown of aged, unnecessary, and harmful proteins into their amino acid residues. Lysosomes, which were previously considered protein-degrading garbage boxes, are now recognized as crucial intracellular sensors that play significant roles in normal signaling and disease pathogenesis. Lysosomes participate in various processes, including digestion, recycling, exocytosis, calcium signaling, nutrient sensing, and wound repair, highlighting the importance of ion channels in these signaling pathways. This review focuses on different lysosomal ion channels, including those associated with diseases, and provides insights into their cellular functions. By summarizing the existing knowledge and literature, this review emphasizes the need for further research in this field. Ultimately, this study aims to provide novel perspectives on the regulation of lysosomal ion channels and the significance of ion-associated signaling in intracellular functions to develop innovative therapeutic targets for rare and lysosomal storage diseases.

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Section: The Role Of Ion Channels In Maintaining Lysosomal Functionmentioning

confidence: 99%

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

Jung

Kim

Shin

et al. 2023

Korean J Physiol Pharmacol

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“…Also, inhibition of the non-selective Ca 2+ channel, transient receptor potential vanilloid 1, which normally regulates inflammatory responses, attenuates CHIKV infection of a macrophage cell line suggesting the ion channel contributes to viral replication [32]. Ion channels are also required for the efficient replication of several other viruses [33][34][35] . For example, Coronaviruses and Ebola viruses both require 2-pore channel activity for efficient entry into cells via the endocytic pathway because the Ca 2+ transport into endosomes facilitates fusion of the viral envelope with the endosomal membrane and release of the genome into the cytoplasm [36][37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of potassium ion channels reduces Semliki Forest virus genome replication

Russell,

O’Brien,

Gangotia

et al. 2023

Preprint

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Introduction Semliki forest virus (SFV) is a model virus used to investigate the Alphavirus genus, which includes human pathogens Chikungunya virus and Ross River virus. Viruses harness cellular machinery to facilitate various steps of their replicative cycles. Ion channels are one group of cellular proteins required for the efficient replication of some viruses, including Influenza A viruses, Ebola virus and members of the Betacoronavirus genus. This study focussed on understanding SFVs requirement for functional ion channels during replication. Methods The effect of ion channel inhibitors on in vitro SFV infections was measured to investigate the contribution of ion channels in its replication cycle. Results In vitro SFV infections carried out in the presence or absence of different ion channel inhibitors showed broad-range K+ channel inhibitors reproducibly attenuated virus replication and reduced its cytotoxicity in two mammalian cell lines. These broad-range K+ channel inhibitors disrupted an early, post-entry step causing a delay or reduction in SFV protein and RNA synthesis. Screens using inhibitors of specific K+ channel families showed that two-pore domain K+ channel (2pK) inhibitors attenuated SFV replication. Confocal microscopy revealed decreased detection of dsRNA and SFV protein in the presence of inhibitor but no change in RNA and protein colocalisation, which would indicate disruption of replication complexes. Broad-range K+ and 2pK inhibitors decreased viral RNA replication and transcription from the subgenomic promoter. Conclusions K+ channel inhibitors attenuate in vitro SFV replication by inhibiting an early, post-entry step of virus replication, potentially RNA synthesis.

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Antiviral Activity of Pd(II) Complexes with Aminoadamantanes Against Arboviruses

Silva,

Cruz,

Pereira

et al. 2024

ChemistrySelect

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In this paper, we report the synthesis, structural characterization, and antiviral properties of palladium(II) complexes with amantadine (atd) and memantine (mtn). Elemental and mass spectrometric analyses indicated a 1:2 metal/ligand ratio. The single crystal data for Pd‐mtn revealed that the complex adopts a square geometry with the two memantine ligands bonded to Pd(II) by the nitrogen atoms of the NH2 group, in a trans configuration. Computational studies supported a similar structure for Pd‐atd. The complexes were stable in DMSO solution for 24 h. The antiviral properties of Pd‐atd and Pd‐mtn were evaluated against Zika (ZIKV) and Chikungunya (CHIKV) viruses in vitro at their highest noncytotoxic concentrations. The Pd‐atd (at 2 µM) and Pd‐mtn (at 10 µM) complexes were able to impair 76% and 96% of CHIKV replication, respectively, which points the coordination of amantadine and memantine to Pd(II) as a successful strategy to increase their anti‐CHIKV properties. Conversely, the Pd(II) complexes did not significantly inhibit the replication of ZIKV, which confirms the selectivity towards CHIKV. Interaction of the compounds with N‐acetyl‐l‐cysteine, a model disulfide‐containing peptide, and plasmid DNA pointed to Cys‐containing peptides as more likely targets than nucleotides for the complexes.

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Assessing the potential of repurposing ion channel inhibitors to treat emerging viral diseases and the role of this host factor in virus replication

Cited by 5 publications

References 286 publications

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

Inhibition of potassium ion channels reduces Semliki Forest virus genome replication

Antiviral Activity of Pd(II) Complexes with Aminoadamantanes Against Arboviruses

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