Cvill6和Cvill7:从墨西哥蝎子中分离出的Kv1.2离子通道的强效和选择性肽阻断剂
Cvill6 and Cvill7: Potent and Selective Peptide Blockers of Kv1.2 Ion Channel Isolated from Mexican Scorpion .
作者信息
Shakeel Kashmala, Naseem Muhammad Umair, Olamendi-Portugal Timoteo, Zamudio Fernando Z, Possani Lourival Domingos, Panyi Gyorgy
机构信息
Department of Biophysics and Cell Biology, Faculty of Medicine, Research Center for Molecular Medicine, University of Debrecen, Egyetem ter. 1, 4032 Debrecen, Hungary.
Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnologia, Universidad Nacional Autónoma de México, Av. Universidad 2001, Cuernavaca 62210, Mexico.
出版信息
Toxins (Basel). 2025 Jun 4;17(6):279. doi: 10.3390/toxins17060279.
Scorpion venoms are a rich source of peptides that modulate the activity of ion channels and can serve as a new drug for channelopathies. Cvill6 and Cvill7 are two new peptides isolated from the venom of with MW of 4277 Da and 4287 Da and they consist of 38 and 39 amino acids, respectively, including six cysteines. Sequence alignment revealed high similarity with members of the α-KTx2 subfamily of potassium channel toxins. In electrophysiology, Cvill7 potently inhibited Kv1.2 ion channels with an IC of 16 pM and Kv1.3 with an IC of 7.2 nM. In addition, it exhibited partial activity on KCa3.1 and Kv1.1, with 16% and ~34% inhibition at 100 nM, respectively. In contrast, Cvill6 blocked Kv1.2 with low affinity (IC of 3.9 nM) and showed modest inhibition of Kv1.3 (11%) and KCa3.1 (~27%) at 100 nM concentration. Neither peptide showed any activity against other K channels tested in this study (Kv1.5, Kv11.1, KCa1.1, and KCa2.2). Notably, Cvill7 has a remarkable affinity for Kv1.2 and high selectivity of 450-fold over Kv1.3 and 12,000-fold over Kv1.1. These pharmacological properties make Cvill7 a potential candidate to target Kv1.2 gain of function (GOF)-related channelopathies such as epilepsy.
蝎毒是一类富含肽的物质,这些肽可调节离子通道的活性,并可作为治疗通道病的新药。Cvill6和Cvill7是从蝎毒中分离出的两种新肽,分子量分别为4277 Da和4287 Da,它们分别由38和39个氨基酸组成,包括6个半胱氨酸。序列比对显示,它们与钾通道毒素α-KTx2亚家族的成员具有高度相似性。在电生理学实验中,Cvill7能有效抑制Kv1.2离子通道,IC50为16 pM,对Kv1.3的IC50为7.2 nM。此外,它对KCa3.1和Kv1.1表现出部分活性,在100 nM时抑制率分别约为16%和34%。相比之下,Cvill6对Kv1.2的阻断亲和力较低(IC50为3.9 nM),在100 nM浓度下对Kv1.3(约11%)和KCa3.1(约27%)表现出适度抑制。在本研究中测试的其他钾通道(Kv1.5、Kv11.1、KCa1.1和KCa2.2)上,这两种肽均未表现出任何活性。值得注意的是,Cvill7对Kv1.2具有显著亲和力,对Kv1.3的选择性高达450倍,对Kv1.1的选择性高达12000倍。这些药理学特性使Cvill7成为治疗与Kv1.2功能获得性(GOF)相关的通道病(如癫痫)的潜在候选药物。