Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease

Chandy, George; Norton, Raymond S.

doi:10.1016/j.cbpa.2017.02.015

Cited by 115 publications

(117 citation statements)

References 78 publications

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“…In Stichodactyla helianthus (27). Extensive work has focused on the development of more stable and specific Shk analogous for the treatment of autoimmune diseases (13,29,130,156). These peptides bind tightly into the external vestibule of the channels with 1:1 toxin-channel stoichiometry, occluding the permeation pathway (review in 107,151).…”

Section: Introductionmentioning

confidence: 99%

The secret life of ion channels: Kv1.3 potassium channels and proliferation

Pérez-Garcı́a

Cidad

López‐López

2018

American Journal of Physiology-Cell Physiology

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Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They modulate membrane potential controlling K fluxes, sense changes in potential, and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the "membrane potential model," membrane hyperpolarization resulting from Kv1.3 activation provides the driving force for Ca influx required to activate Ca-dependent transcription. This model explains most of the data obtained from several cells from the immune system. In the "voltage sensor model," Kv1.3 channels serve mainly as sensors that transduce electrical signals into biochemical cascades, independently of their effect on membrane potential. Kv1.3-dependent proliferation of vascular smooth muscle cells (VSMCs) could fit this model. Finally, in the "channelosome balance model," the master switch determining proliferation may be related to the control of the Kv1.3 to Kv1.5 ratio, as described in glial cells and also in VSMCs. Since the three mechanisms cannot function independently, these models are obviously not exclusive. Nevertheless, they could be exploited differentially in different cells and tissues. This large functional flexibility of Kv1.3 channels surely gives a new perspective on their functions beyond their elementary role as ion channels, although a conclusive picture of the mechanisms involved in Kv1.3 signaling to proliferation is yet to be reached.

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Section: Introductionmentioning

confidence: 99%

The secret life of ion channels: Kv1.3 potassium channels and proliferation

Pérez-Garcı́a

Cidad

López‐López

2018

American Journal of Physiology-Cell Physiology

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“…It has been demonstrated that in the effector memory T (T EM ) cell population, the degree of Kv1.3 expression is a measure of cell activation, with greater Kv1.3 numbers/cell following repeated stimulation and that the channel is required for the maintenance of the T EM cell phenotype [6]. These properties make Kv1.3 channels on T lymphocytes an attractive therapeutic target for autoimmune diseases (reviewed recently in [7]). Recent data suggest that the degree of Kv1.3 dependence is mediated by antigen exposure history, that chronically activated autoreactive T cells are primarily dependent on Kv1.3, and that conversion to Kv1.3 dependency is stable [8].…”

Section: Introductionmentioning

confidence: 99%

Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial

et al. 2017

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BackgroundDalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis.ObjectiveThe primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild-to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations.MethodsPatients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires.ResultsThe most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells.LimitationsThe study was small and drug treatment was for a short duration (4 weeks).ConclusionThis study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted.

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“…Blocking K V 1.3 channels in T EM cells blocks their activation and proliferation. As T EM cells are key mediators of autoimmune diseases, K V 1.3 blockers are attractive leads as a new class of therapeutic for these conditions [ 43 , 44 ].…”

Section: Potassium Channel Blockers From Sea Anemones: Therapeuticmentioning

confidence: 99%

“…It is expected to begin Phase 2a trails in 2018. Dalazatide is being advanced as a treatment for various autoimmune diseases, including inclusion body myositis, lupus, ANCA vasculitis, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, type 1 diabetes and inflammatory bowel diseases [ 44 , 45 ]. New analogues of ShK with good selectivity for K V 1.3 over other K V 1 channels have also been developed [ 60 , 61 , 62 , 63 , 64 ].…”

Section: Potassium Channel Blockers From Sea Anemones: Therapeuticmentioning

confidence: 99%

Sea Anemones: Quiet Achievers in the Field of Peptide Toxins

Prentis

Pavasovic

Norton

2018

Toxins

104

139

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Sea anemones have been understudied as a source of peptide and protein toxins, with relatively few examined as a source of new pharmacological tools or therapeutic leads. This is surprising given the success of some anemone peptides that have been tested, such as the potassium channel blocker from Stichodactyla helianthus known as ShK. An analogue of this peptide, ShK-186, which is now known as dalazatide, has successfully completed Phase 1 clinical trials and is about to enter Phase 2 trials for the treatment of autoimmune diseases. One of the impediments to the exploitation of sea anemone toxins in the pharmaceutical industry has been the difficulty associated with their high-throughput discovery and isolation. Recent developments in multiple 'omic' technologies, including genomics, transcriptomics and proteomics, coupled with advanced bioinformatics, have opened the way for large-scale discovery of novel sea anemone toxins from a range of species. Many of these toxins will be useful pharmacological tools and some will hopefully prove to be valuable therapeutic leads.Keywords: sea anemone; peptide; ShK; potassium channel; autoimmune disease; genomics; transcriptomics; proteomics; evolution Key Contribution: The sea anemone peptide ShK highlights the potential of these venomous animals to produce valuable therapeutic leads, and the abundance in nature of peptides related to ShK suggests that this scaffold can support a range of functions. Current genomic, transcriptomic and proteomic studies of sea anemones promise to greatly expand the number of ShK analogues and to identify a range of novel peptide families.

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Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease

Cited by 115 publications

References 78 publications

The secret life of ion channels: Kv1.3 potassium channels and proliferation

The secret life of ion channels: Kv1.3 potassium channels and proliferation

Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial

Sea Anemones: Quiet Achievers in the Field of Peptide Toxins

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