Scorpion Toxins Specific for Potassium (K+) Channels: A Historical Overview of Peptide Bioengineering

Abstract

Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K+) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the correlation between mutations, altered regulation and a number of human pathologies. Radio- and fluorescently-labeled toxin isoforms have contributed to localization studies of channel subtypes in expressing cells, and have been further used in competitive displacement assays for the identification of additional novel ligands for use in research and medicine. Chimeric toxins have been designed from multiple peptide scaffolds to probe channel isoform specificity, while advanced epitope chimerization has aided in the development of novel molecular therapeutics. Peptide backbone cyclization has been utilized to enhance therapeutic efficiency by augmenting serum stability and toxin half-life in vivo as a number of K+-channel isoforms have been identified with essential roles in disease states ranging from HIV, T-cell mediated autoimmune disease and hypertension to various cardiac arrhythmias and Malaria. Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics.

Scorpion venom components that affect ion-channels function

“…Other residues facing the channel vestibule also contribute to the binding (Rodríguez de la Vega et al, 2013). This interaction has been determined in studies of structure and function of various toxins such as Agitoxin, Charybdotoxin, Noxiustoxin (Bergeron and Bingham, 2012); (2) the “intermediate” mode, where a patch of the basic residues of the toxin (Tamapin from M. tamulus) make contacts with a negatively charged extracellular loop of KCa2 channel stabilizing the binding (Rodriguez de la Vega et al, 2013; Andreotti et al, 2005). …”

Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels

“…This property may allow the therapeutic application of such molecules in various diseases such as asthma, cardiac arrhythmia, hypertension and T-cell mediated autoimmune diseases (Bergeron and Bingham, 2012;Jimenez-Vargas et al, 2012; …”

Evolution of alternative methodologies of scorpion antivenoms production

“…Toxins affecting potassium channels are more diverse and function by blocking or inactivating these channels. They are further classified into a-KTx, b-KTx, g-KTx and к-Ktx in addition to their pharmacological action and the type of ion channel affected (Carbone et al, 1982;Possani et al, 1982 Bergeron andBingham, 2012). Other neurotoxins have been also been shown to affect chloride and calcium channels (Mouhat et al, 2004;Q4 Norton and Mcdonough, 2008).…”