title: Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune diseases.
abstract: CCR7- effector memory T (TEM) lymphocytes are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. These cells express Kv1.3 potassium channels that play a major role in their activation. Blocking these channels preferentially inhibits the activation of CCR7- TEM cells, with little or no effects on CCR7+ naïve and central memory T cells. Blockers of lymphocyte Kv1.3 channels 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 lacks selectivity for Kv1.3 channels over closely-related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK led to models of ShK docked with the channel. This knowledge was valuable in the development of new ShK analogs 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 further evaluation as potential immunomodulators for the treatment of autoimmune diseases.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA. beeton@bcm.edu
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D003064:Cnidarian Venoms / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy* / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015202:Protein Engineering; D055550:Protein Stability; D054400:Receptors, CCR7 / Q000378:metabolism; D012615:Sea Anemones / Q000378:metabolism; D051637:Shaker Superfamily of Potassium Channels / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: C515370:CCR7 protein, human; D003064:Cnidarian Venoms; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D054400:Receptors, CCR7; C095391:ShK neurotoxin; D051637:Shaker Superfamily of Potassium Channels