Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom

Sonia Maatoug (1, 2) , Amani Cheikh (1, 2) , Oussema Khamessi (3, 2) , Hager Tabka (1, 2, 4) , Zied Landoulsi (1, 2) , Jean-Marie Guigonis (5) , Sylvie Diochot (6) , Saïd Bendahhou (7) , Rym Benkhalifa (1, 2)

1 Biomolécules, Venins et Applications Théranostiques [Tunis]
2 UTM - Université de Tunis El Manar
3 LR11IPT08 - Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules
4 UCAR - Université de Carthage (Tunisie)
5 TIRO-MATOs UMR E4320 - Transporteurs et Imagerie, Radiothérapie en Oncologie et Mécanismes biologiques des Altérations du Tissu Osseux
6 IPMC - Institut de pharmacologie moléculaire et cellulaire
7 LP2M - Laboratoire de PhysioMédecine Moléculaire

The voltage-gated K+ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In the present study, we focused on the biochemical and pharmacological characterization of the component in AahG50 scorpion venom that potently and selectively blocks the Kv3.1 channels. We used a combined optimization through advanced biochemical purification and patch-clamp screening steps to characterize the peptide in AahG50 active on Kv3.1 channels. We described the inhibitory effect of a toxin on Kv3.1 unitary current in black lipid bilayers. In silico, docking experiments are used to study the molecular details of the binding. We identified the first scorpion venom peptide inhibiting Kv3.1 current at 170 nM. This toxin is the alpha-KTx 15.1, which occludes the Kv3.1 channel pore by means of the lysine 27 lateral chain. This study highlights, for the first time, the modulation of the Kv3.1 by alpha-KTx 15.1, which could be an interesting starting compound for developing therapeutic biomolecules against Kv3.1-associated diseases.

Mots clés: Kv3.1 channel; Androctonus australis hector venom; open channel blocker; alpha-KTx

Domaines: Pharmacologie; Neurobiologie

Sonia Maatoug, Amani Cheikh, Oussema Khamessi, Hager Tabka, Zied Landoulsi, et al.. Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom. International Journal of Molecular Sciences, 2021, 22 (22), pp.12290. ⟨10.3390/ijms222212290⟩. ⟨hal-03455259⟩