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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.

Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesity-inducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased β-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance.

Obesity is a global health problem and there is a pressing need for safe therapeutics. Here, we describe the anti-obesity effects of ShK-186, a Kv1.3-selective peptide inhibitor with picomolar potency and an excellent safety profile in rodents and monkeys. C57BL/J mice fed a diet containing high fat (21%) diet and fructose solution (60%) were administered ShK-186 (20, 100 or 500 μg/kg) or vehicle on alternate days by subcutaneous injection. ShK-186-treatment caused a dose-dependent reduction in weight gain over the 45-day trial, the maximal weight difference being 30%. ShK-186-treatment reduced plasma levels of triglyceride and free fatty acids without affecting cholesterol, HDL, LDL or glucose. CT scan revealed significant reduction in volume of white adipose tissue (WAT) in ShK-186-treated mice compared to vehicle-controls. However, histology revealed no difference in cell size and fat content of white fat cells. In metabolic cage experiments, ShK-186-treatment increased cumulative intake of food and fluid compared to vehicle-treated mice, especially during the light-cycle. Furthermore, their respiratory exchange ratio and energy expenditure were also higher. In PET experiments, ShK-186 treatment increased uptake of 18-fluoro-deoxyglucose (18FDG) by brown adipose tissue (BAT) and skeletal muscle compared to vehicle-controls; pre-administration of the beta-adrenoceptor blocker propranolol (5mg/kg) inhibited 18FDG uptake by BAT but not skeletal muscle. ShK-186's anti-obesity effect appears to be mediated by activation of BAT and/or skeletal muscle, two important thermogenic tissues in the body.