KV1.2-Selective Peptide with High Affinity.

The isoform of voltage-gated potassium channels K_V1.2 is of interest because mutations in its gene are associated with various diseases, such as ataxia and epilepsy. Selective ligands are needed to study the function of K_V1.2 in health and disease. In our work, we obtained such a ligand based on the known scorpion peptide toxin, charybdotoxin (ChTx, α-KTx1.1) from the venom of Leiurus hebraeus, by introducing a single amino acid substitution M29I into its structure. ChTx_M29I peptide was produced in a bacterial expression system. Its pharmacological characterization was carried out in Xenopus laevis frog oocytes expressing a panel of human K_V1 channels. We found that, compared to the parent toxin, ChTx_M29I peptide showed lower affinity for K_V1.1, 1.3, and 1.6 channels, while its activity against K_V1.2 increased manifold. We attribute this effect to the interaction of the peptide with a specific channel residue (V381 in K_V1.2). If there is a relatively small residue at this position, then an advantageous contact is formed that increases the affinity. ChTx_M29I peptide studied by us presents one of the highest affinity (with a half-maximal inhibitory concentration IC₅₀ ≈ 6 pM) and selectivity among K_V1.2 ligands (affinity for other isoforms is lower by 680 times or more). [ABSTRACT FROM AUTHOR]