Powerful and selective peptide blockers of the KV1.2 ion channel isolated from the Mexican scorpion centuroids Villegasi

Abstract

Scorpion poisons are a rich source of peptides that modulate the activity of ionic channels and can serve as a new drug for canalopathies. CVILL6 and CVILL7 are two new peptides isolated from the poison of Villegasi centuroids With MW of 4277 DA and 4287 gives and consist of 38 and 39 amino acids, respectively, including six cysteines. The alignment of the sequence revealed a high similarity with the members of the α-KTX2 subfamily of toxins of the potassium channel. In electrophysiology, CVILL7 potently inhibited the ionic KV1.2 channels with an IC50 16 PM and KV1.3 with an IC50 7.2 nm. In addition, it exhibited partial activity in Kca3.1 and KV1.1, with ~ 16% and ~ 34% inhibition at 100 nm, respectively. In contrast, CVill6 blocked KV1.2 with low affinity (IC50 of 3.9 Nm) and showed a modest inhibition of KV1.3 (~ 11%) and Kca3.1 (~ 27%) to a concentration of 100 nm. None of the peptides showed any activity against other K+ + The channels tested in this study (KV1.5, KV11.1, KCA1.1 and KCA2.2). In particular, CVILL7 has a remarkable affinity for KV1.2 and a high selectivity of 450 times on KV1.3 and 12,000 times on KV1.1. These pharmacological properties make CVILL7 a potential candidate to aim at KV1.2 Function gain (GOF) canalopathies related to epilepsy.