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Abstract
The potassium channel Kv1.3 is an attractive pharmacological target for T-cell-mediated
autoimmune diseases, and specific and selective peptidic blockers of Kv1.3 channels
have served as valuable therapeutic leads for treating these diseases. Here, we found
a new peptide toxin, J123, with 43 amino acids including six cysteine residues by
screening the venomous cDNA library of scorpion Buthus martensii Karsch, which has
been used as traditional medicine in China for more than 2000 years. The sequence
analysis suggested that peptide J123 constituted a new member of the alpha-KTx toxins.
The electrophysiological experiments further indicated that peptide J123 has a novel
pharmacological profiles: it blocked Kv1.3 channel with high potency (IC50=0.79 nM),
and exhibited good selectivity on Kv1.3 over Kv1.1 (>1000-fold) and Kv1.2 (about 30-fold),
respectively. Furthermore, peptide J123 had no activity on SKCa2 and SKCa3 channels
at micromolar concentration level. Based on the pharmacological activities, the possible
channel-interacting surface of peptide J123 was also predicted by molecular modeling
and docking. All these data not only enrich the knowledge of the structure-function
relationship of the new Kv1.3-speicific peptide but also present a potential drug
candidate for selectively targeting Kv1.3 channels.