Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels

The voltage-gated potassium channel, Kv1.3, is specifically expressed on hu man lymphocytes, where it controls membrane potential and calcium influx. B lockade of Kv1.3 channels by margatoxin was previously shown to prevent T c ell activation and attenuate immune responses in vivo. In the present study , a triterpene natural product, correolide, was found to block Kv1.3 channe ls in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-depen dent manner. More potent analogs were evaluated for pharmacokinetic profile s and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im , and both compounds suppressed DTH responses, demonstrating that small mol ecule blockers of Kv1.3 channels can act as immunosuppressive agents in viv o. These studies establish correolide and its derivatives as novel immunosu ppressants. (C) 1999 Academic Press.