title: Expanding the pharmacological profile of κ-hefutoxin 1 and analogues: A focus on the inhibitory effect on the oncogenic channel Kv10.1.
abstract: Peptide toxins, such as scorpion peptides, are interesting lead compounds in the search for novel drugs. In this paper, the focus is on the scorpion peptide κ-hefutoxin 1. This peptide displays a cysteine-stabilized helix-loop-helix fold (CSα/α) and is known to be a weak Kv1.x inhibitor. Due to the low affinity of κ-hefutoxin 1 for these channels, it is assumed that the main target(s) of κ-hefutoxin 1 remain(s) unknown. In order to identify novel targets, electrophysiological measurements and antifungal assays were performed. The effect of κ-hefutoxin 1 was previously evaluated on a panel of 11 different voltage-gated potassium channels. Here, we extended this target screening with the oncogenic potassium channel Kv10.1. κ-Hefutoxin 1 was able to inhibit this channel in a dose-dependent manner (IC50∼26μM). Although the affinity is rather low, this is the first peptide toxin ever described to be a Kv10.1 inhibitor. The structure-activity relationship of κ-hefutoxin 1 on Kv10.1 was investigated by testing eight κ-hefutoxin 1 variants using the two-electrode voltage clamp technique. Several important amino acid residues were identified; the functional dyad residues (Tyr5and Lys19), N-terminal residues (Gly1and His2) and the amidated C-terminal residue (Cys22). Since the CSα/α fold is also found in a class of antifungal plant peptides, the α-hairpinines, we investigated the antifungal activity of κ-hefutoxin 1. κ-Hefutoxin 1 showed low activity against the plant pathogen Fusarium culmorum and no activity against three other yeast and fungal species, even at high concentrations (∼100μM).
authors: Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, PO Box 922, 3000 Leuven, Belgium. Electronic address: lien.moreels@pharm.kuleuven.be.
authors: Lien
authors: L
authors: Moreels
authors: Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, PO Box 922, 3000 Leuven, Belgium. Electronic address: steve.peigneur@pharm.kuleuven.be.
authors: Steve
authors: S
authors: Peigneur
authors: Department of Environmental Science, Fukuoka Women's University, Fukuoka 813-8529, Japan. Electronic address: youko@fwu.ac.jp.
authors: Yoko
authors: Y
authors: Yamaguchi
authors: Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, PO Box 2460, 3001 Leuven, Belgium. Electronic address: kim.vriens@vib-kuleuven.be.
authors: Kim
authors: K
authors: Vriens
authors: Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Campus Gasthuisberg, O&N1, Herestraat 49, PO Box 901, 3000 Leuven, Belgium. Electronic address: etienne.waelkens@kuleuven.be.
authors: Etienne
authors: E
authors: Waelkens
authors: Group of Peptide Biology and Evolution, State Key Laboratory of Integrated Management of Pest Insects & Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. Electronic address: zhusy@ioz.ac.cn.
authors: Shunyi
authors: S
authors: Zhu
authors: Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, PO Box 2460, 3001 Leuven, Belgium. Electronic address: karin.thevissen@kuleuven.be.
authors: Karin
authors: K
authors: Thevissen
authors: Centre of Microbial and Plant Genetics, KU Leuven, Kasteelpark Arenberg 20, PO Box 2460, 3001 Leuven, Belgium; VIB Department of Plant Systems Biology, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: bruno.cammue@biw.vib-kuleuven.be.
authors: Bruno P A
authors: BPA
authors: Cammue
authors: Department of Environmental Science, Fukuoka Women's University, Fukuoka 813-8529, Japan. Electronic address: sato@fwu.ac.jp.
authors: Kazuki
authors: K
authors: Sato
authors: Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, PO Box 922, 3000 Leuven, Belgium. Electronic address: jan.tytgat@pharm.kuleuven.be.
authors: Jan
authors: J
authors: Tytgat
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs; D009865:Oocytes; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D012604:Scorpion Venoms / Q000494:pharmacology*; D013172:Spores, Fungal / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D015003:Yeasts / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; C586277:kappa-hefutoxin 1, Heterometrus fulvipes; D003545:Cysteine
keywords: Antifungal assays; Cancer; K(v)10.1; Potassium channel; Scorpion; κ-Hefutoxin 1