title: Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases.
abstract: Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels--Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Cl(swell)--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.
authors.affiliation: Department of Physiology and Biophysics, UC Irvine, Irvine, CA 92697, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Chi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Tarcha
authors.forename: Luz M
authors.initials: LM
authors.lastname: Londono
authors.forename: Brian
authors.initials: B
authors.lastname: Sims-Fahey
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Upadhyay
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Lakey
authors.forename: Shawn
authors.initials: S
authors.lastname: Iadonato
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D003064:Cnidarian Venoms / Q000493:pharmacokinetics / Q000494:pharmacology*; D064420:Drug-Related Side Effects and Adverse Reactions; D007155:Immunologic Factors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012615:Sea Anemones
chemical_list: D003064:Cnidarian Venoms; D007155:Immunologic Factors; D007473:Ion Channels; C095391:ShK neurotoxin