K+ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom.
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.
Mouhat
Stéphanie
S
Laboratoire Cellpep S.A., 13-15 Rue Ledru-Rollin, 13015 Marseille, France.
Visan
Violeta
V
Ananthakrishnan
S
S
Wulff
Heike
H
Andreotti
Nicolas
N
Grissmer
Stephan
S
Darbon
Hervé
H
De Waard
Michel
M
Sabatier
Jean-Marc
JM
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
C104504:OSK1 toxin, Orthochirus scrobiculosus; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012604:Scorpion Venoms; D014118:Toxins, Biological