The therapeutic potential for targetting potassium channels: are dendrotoxins a suitable basis for drug design?

Voltage-dependent potassium ion channels have been implicated in several diseases of genetic or autoimmune origin. There are genetic defects of specific potassium channel genes in episodic ataxia with myokymia, long QT syndrome, Jervell-Lange-Nielsen syndrome, and familial hyperinsulinemic hypoglycemia of infancy. Antibodies against voltage-gated potassium channels have been detected in Isaacs syndrome (acquired neuromyotonia). Voltage-gated potassium channels have also been regarded as therapeutic targets for immuno-suppressants (targetting Kv1.3 channels) and in some neurodegenerative diseases (targetting Kv1.1 or 1.2 channels). Specific blockers of potassium channels may be designed from an understanding of the molecular recognition properties of highly specific potassium channel blocking toxins such as dendrotoxin. The dendrotoxin family of toxins and their genetic relatives in the Kunitz family of proteinase inhibitors have been studied extensively in recent years. Structural studies and functional studies with mutated toxins provide information that should help the rational design of analogues with the desired properties.