Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases

Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels—Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Clswell—in lymphocytes that initiates and maintains the calcium signaling cascade required for activation. The expression pattern of these channels changes during lymphocyte activation and differentiation, allowing the functional network to adapt during an immune response. The Kv1.3 channel is of interest because it plays a critical role in subsets of T and B lymphocytes implicated in autoimmune disorders. The ShK toxin from the sea anemone Stichodactyla helianthus is a potent blocker of Kv1.3. ShK-186, a synthetic analog of ShK, is being developed as a therapeutic for autoimmune diseases, and is scheduled to begin first-in-man phase-1 trials in 2011. This review describes the journey that has led to the development of ShK-186.

► ShK-186 is a 37-residue synthetic derivative of ShK, a peptide toxin from the sea anemone Stichodactyla helianthus.
►  ShK-186 blocks Kv1.3 potassium channels with picomolar affinity and with a high degree of specificity.
► Kv1.3 potassium channels play a critical role in regulating the function of effector-memory T cells and class-switched memory B cells that are implicated in autoimmune diseases.
► ShK-186 has a good safety profile in rats and it ameliorates disease in rat models of multiple sclerosis and rheumatoid arthritis.
► ShK-186 is being developed as a therapeutic for autoimmune diseases and phase 1 human trials are planned for the near future.