Abstract
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, Kv1.2, Kv1.3 channels potently and KCa3.1 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 Kv 1.3 channel, with an IC50 value of 0.003 nM, without loss of activity on KCa3.1 channel. These data suggest that OSK1 or [K16,D20]-OSK1 could serve as leads for the design and production of new immunosuppressive drugs.
Original language | English (US) |
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Pages (from-to) | 95-104 |
Number of pages | 10 |
Journal | Biochemical Journal |
Volume | 385 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2005 |
Keywords
- Ca-activated K channel
- OSK1
- Peptide synthesis
- Scorpion toxin
- Voltage-gated K channel
ASJC Scopus subject areas
- Biochemistry