Article

Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease

Kineta Inc., 219 Terry Ave N., Suite 300, Seattle, WA 98109-5208, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 05/2012; 342(3):642-53. DOI: 10.1124/jpet.112.191890
Source: PubMed

ABSTRACT The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an ¹¹¹In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC₅₀ value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.

Download full-text

Full-text

Available from: Michael W Pennington, Sep 01, 2015
0 Followers
 · 
432 Views
 · 
607 Downloads
  • Source
    • "A further potent K v 1.3 blocking toxin is found in the sea anemone Stichodactyla helianthus. Recombinant peptides that are derived from its Stichodactyla toxin (ShK) are evaluated as potential novel therapeutics for autoimmune diseases (Beeton et al., 2008; Pennington et al., 2009; Tarcha et al., 2012) but being peptides they need to be administered per injection and have unfavorable pharmacokinetics with very short half-lives. Both kaliotoxin and ShK block the potassium pore of voltage gated potassium channels with higher affinity to K v 1.3 over the other subtypes (Judge & Bever, 2006), hence providing some immune specificity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 7.75 Impact Factor
  • Source
    • "The Kv1.3 channel was modeled by Smith and collaborators,24 who assessed a model of the pore and vestibule of the Kv1.3 channel based on the crystallographic structure of the K+ channel from Streptomyces lividans (Kcsa)26 and subsequently, modeled with MODELLER software.38 This Kv1.3 channel has been useful to determine important interactions that were subsequently verified in animal models with positive result, which indicates it is a trustable computational model.8,39 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sea anemone neurotoxins are peptides that interact with Na(+) and K(+) channels, resulting in specific alterations on their functions. Some of these neurotoxins (1ROO, 1BGK, 2K9E, 1BEI) are important for the treatment of about 80 autoimmune disorders because of their specificity for Kv1.3 channel. The aim of this study was to identify the common residues among these neurotoxins by computational methods, and establish whether there is a pattern useful for the future generation of a treatment for autoimmune diseases. Our results showed eight new key common residues between the studied neurotoxins interacting with a histidine ring and the selectivity filter of the receptor, thus showing a possible pattern of interaction. This knowledge may serve as an input for the design of more promising drugs for autoimmune treatments.
    Bioinformatics and biology insights 04/2014; 8:73-81. DOI:10.4137/BBI.S13403
  • Source
    • "The compounds yielded similar results, confirming that their effects on NK cells are caused specifically through KCa3.1 blockade. We similarly used ShK-186 [40] and PAP-1 [16] to ensure the observed effects are due to Kv1.3 block. ShK-186 and PAP-1 concentration of 70 pM and 2 nM are sufficient to block 50% of the Kv1.3 current of NK cells and concentrations of 20 nM of TRAM-34 and 11 nM of NS6180 are sufficient to block 50% of their KCa3.1 currents. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells are large granular lymphocytes that participate in both innate and adaptive immune responses against tumors and pathogens. They are also involved in other conditions, including organ rejection, graft-versus-host disease, recurrent spontaneous abortions, and autoimmune diseases such as multiple sclerosis. We demonstrate that human NK cells express the potassium channels Kv1.3 and KCa3.1. Expression of these channels does not vary with expression levels of maturation markers but varies between adherent and non-adherent NK cell subpopulations. Upon activation by mitogens or tumor cells, adherent NK (A-NK) cells preferentially up-regulate KCa3.1 and non-adherent (NA-NK) cells preferentially up-regulate Kv1.3. Consistent with this different phenotype, A-NK and NA-NK do not display the same sensitivity to the selective KCa3.1 blockers TRAM-34 and NS6180 and to the selective Kv1.3 blockers ShK-186 and PAP-1 in functional assays. Kv1.3 block inhibits the proliferation and degranulation of NA-NK cells with minimal effects on A-NK cells. In contrast, blocking KCa3.1 increases the degranulation and cytotoxicity of A-NK cells, but not of NA-NK cells. TRAM-34, however, does not affect their ability to form conjugates with target tumor cells, to migrate, or to express chemokine receptors. TRAM-34 and NS6180 also increase the proliferation of both A-NK and NA-NK cells. This results in a TRAM-34-induced increased ability of A-NK cells to reduce in vivo tumor growth. Taken together, our results suggest that targeting KCa3.1 on NK cells with selective blockers may be beneficial in cancer immunotherapy.
    PLoS ONE 10/2013; 8(10):e76740. DOI:10.1371/journal.pone.0076740 · 3.23 Impact Factor
Show more