title: Targeting the ion channel Kv1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life.
abstract: Ion channels are an attractive class of drug targets, but progress in developing inhibitors for therapeutic use has been limited largely due to challenges in identifying subtype selective small molecules. Animal venoms provide an alternative source of ion channel modulators, and the venoms of several species, such as scorpions, spiders and snails, are known to be rich sources of ion channel modulating peptides. Importantly, these peptides often bind to hyper-variable extracellular loops, creating the potential for subtype selectivity rarely achieved with small molecules. We have engineered scorpion venom peptides and incorporated them in fusion proteins to generate highly potent and selective Kv1.3 inhibitors with long in vivo half-lives. Kv1.3 has been reported to play a role in human T cell activation, and therefore, these Kv1.3 inhibitor fusion proteins may have potential for the treatment of autoimmune diseases. Our results support an emerging approach to generating subtype selective therapeutic ion channel inhibitors.
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121. Electronic address: wedward3@its.jnj.com.
authors.forename: Wilson
authors.initials: W
authors.lastname: Edwards
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Fung-Leung
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Chichi
authors.initials: C
authors.lastname: Huang
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Ellen
authors.initials: E
authors.lastname: Chi
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Nancy
authors.initials: N
authors.lastname: Wu
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Maher
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Bonesteel
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Judith
authors.initials: J
authors.lastname: Connor
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Ross
authors.initials: R
authors.lastname: Fellows
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Jerry
authors.initials: J
authors.lastname: Lee
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Karen
authors.initials: K
authors.lastname: Ngo
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Brian
authors.initials: B
authors.lastname: Scott
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
authors.affiliation: Janssen Research and Development, LLC, San Diego, California 92121.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
mesh_terms: D000818:Animals; D060829:Arthropod Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems; D006207:Half-Life; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015202:Protein Engineering; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D060829:Arthropod Proteins; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms
keywords: Drug Discovery; Immunology; Peptides; Potassium Channel; T-cell