Targeting the Ion Channel Kv1.3 with Scorpion Venom Peptides Engineered for Potency, Selectivity, and Half-life

Edwards, Wilson B.; Fung-Leung, Wai-Ping; Huang, Chichi; Chi, Ellen; Wu, Nancy; Liu, Yi; Maher, Michael P.; Bonesteel, Rachelle; Connor, Judith; Fellows, Ross; Garcia, Elena Alexandra; Lee, Jerry; Lu, Lu; Ngo, Karen; Scott, Brian; Zhou, Hong; Swanson, Ronald V.; Wickenden, Alan D.

doi:10.1074/jbc.m114.568642

Cited by 28 publications

(31 citation statements)

References 31 publications

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“…The potency of OsK1 peptide against voltage-gated currents in human primary CD4 T cells and CHO cells stably transfected with recombinant human Kv1.3 was measured in a manual patch clamp assay, as previously described [24]. Briefly, T cells or transfected CHO cells were plated onto glass coverslips in a bath on the stage of an inverted microscope and perfused (approximately 1ml/min) with extracellular solution of the following composition: 137mM NaCl, 2mM CaCl 2 , 5.4mM KCl, 1mM MgCl 2 , 5mM glucose, and 10mM HEPES, 0.1% bovine serum albumin, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…ShK peptide toxin from the Caribbean sea anemone Stichodactyla helianthus, and members of the α-KTx3 scorpion toxin family, such as OsK1 from the venom of the Central Asian scorpion Orthochirus scrobiculosus and OdK2 from the Iranian scorpion Odonthobuthus doriae, are all potent blockers of Kv1.3 [5, 20–23]. Engineered variants of ShK, OsK1 and OdK2 that potently and selectively inhibit Kv1.3 have also been identified [24, 25]. Recently we reported an engineered Kv261 peptide with sequence derived from OsK1 and OdK2 [24].…”

Section: Introductionmentioning

confidence: 99%

“…Engineered variants of ShK, OsK1 and OdK2 that potently and selectively inhibit Kv1.3 have also been identified [24, 25]. Recently we reported an engineered Kv261 peptide with sequence derived from OsK1 and OdK2 [24]. We demonstrated that Kv261 and its human albumin fusion protein Kv261-HSA-34 are potent and selective Kv1.3 blockers [24].…”

Section: Introductionmentioning

confidence: 99%

“…Recently we reported an engineered Kv261 peptide with sequence derived from OsK1 and OdK2 [24]. We demonstrated that Kv261 and its human albumin fusion protein Kv261-HSA-34 are potent and selective Kv1.3 blockers [24]. …”

Section: Introductionmentioning

confidence: 99%

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T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers

et al. 2017

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Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers

et al. 2017

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“…Based on all this positive animal data, Kineta Inc. completed Phase 1a and 1b studies with ShK-186 in 2014 with no major safety findings and is currently planning to start enrolling patients for trials in psoriatic arthritis and psoriasis later in 2014. Several companies, including Amgen and Janssen, are making efforts to prolong the short half-life of venom peptides like ShK by conjugating them to Fc antibody fragments, making fusion proteins (373) or producing K V 1.3-targeting nanobodies (Ablynx).…”

Section: Ion Channels As Drug Targets For Immunotherapymentioning

confidence: 99%

Ion Channels in Innate and Adaptive Immunity

Feske¹,

Wulff

Skolnik

2015

Annu. Rev. Immunol.

572

616

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Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

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Autocrine‐Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries

Zhang

Xie

et al. 2016

Angewandte Chemie

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Targeting the Ion Channel Kv1.3 with Scorpion Venom Peptides Engineered for Potency, Selectivity, and Half-life

Cited by 28 publications

References 31 publications

T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers

T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers

Ion Channels in Innate and Adaptive Immunity

Autocrine‐Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries

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