CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases
التفاصيل البيبلوغرافية
العنوان:
CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases
Effector memory T lymphocytes, which are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis, express Kv1.3 potassium channels, which play a major role in their activation. Blockers of lymphocyte Kv1.3 channels preferentially inhibit the activation of these cells and therefore show considerable potential as therapeutics for autoimmune diseases. ShK, a 35-residue polypeptide isolated from the Caribbean sea anemone Stichodactyla helianthus, blocks Kv1.3 channels at picomolar concentrations. Although ShK was effective in treating rats with delayed type hypersensitivity and a model of multiple sclerosis, it lacked selectivity for Kv1.3 channels over closely related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK provided the basis for developing new ShK analogues with improved selectivity and increasing stability, which have proven efficacious in preventing and/or treating animal models of delayed type hypersensitivity, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis without inducing generalized immunosuppression. They are currently undergoing clinical evaluation as potential immunomodulators for the treatment of autoimmune diseases.
