title: K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom.
abstract: OSK1 (alpha-KTx3.7) is a 38-residue toxin cross-linked by three disulphide bridges that was initially isolated from the venom of the Asian scorpion Orthochirus scrobiculosus. OSK1 and several structural analogues were produced by solid-phase chemical synthesis, and were tested for lethality in mice and for their efficacy in blocking a series of 14 voltage-gated and Ca2+-activated K+ channels in vitro. In the present paper, we report that OSK1 is lethal in mice by intracerebroventricular injection, with a LD50 (50% lethal dose) value of 2 microg/kg. OSK1 blocks K(v)1.1, K(v)1.2, K(v)1.3 channels potently and K(Ca)3.1 channel moderately, with IC50 values of 0.6, 5.4, 0.014 and 225 nM respectively. Structural analogues of OSK1, in which we mutated positions 16 (Glu16-->Lys) and/or 20 (Lys20-->Asp) to amino acid residues that are conserved in all other members of the alpha-KTx3 toxin family except OSK1, were also produced and tested. Among the OSK1 analogues, [K16,D20]-OSK1 (OSK1 with Glu16-->Lys and Lys20-->Asp mutations) shows an increased potency on K(v)1.3 channel, with an IC50 value of 0.003 nM, without loss of activity on K(Ca)3.1 channel. These data suggest that OSK1 or [K16,D20]-OSK1 could serve as leads for the design and production of new immunosuppressive drugs.
authors.affiliation: Laboratoire Cellpep S.A., 13-15 Rue Ledru-Rollin, 13015 Marseille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mouhat
authors.forename: Violeta
authors.initials: V
authors.lastname: Visan
authors.forename: S
authors.initials: S
authors.lastname: Ananthakrishnan
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.forename: Stephan
authors.initials: S
authors.lastname: Grissmer
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007276:Injections, Intraventricular; D007928:Lethal Dose 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015221:Potassium Channels / Q000378:metabolism*; D012604:Scorpion Venoms / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012605:Scorpions / Q000737:chemistry*; D014118:Toxins, Biological / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C104504:OSK1 toxin, Orthochirus scrobiculosus; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012604:Scorpion Venoms; D014118:Toxins, Biological