K⁺ channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom

OSK1 (α-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 Ca ²⁺-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 μg/kg. OSK1 blocks K _v 1.1, K_v1.2, K_v1.3 channels potently and K_Ca3.1 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 α-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_Ca3.1 channel. These data suggest that OSK1 or [K₁₆,D₂₀]-OSK1 could serve as leads for the design and production of new immunosuppressive drugs.