Improving Ion Channel Drug Discovery with a C. elegans HTS Screen

Sudden cardiac death is a major cause of mortality in the western world. Changes in currents directing the cardiac action potential is the single largest predisposing factor triggering lethal arrhythmias and heart failure. Voltage-gated K⁺ channels are essential for controlling action potential repolarization and frequency in muscles, neurons and other excitable cells. Kv4.3 is the major transient outward K⁺ channel component in ventricle myocytes, making it a particular interesting therapeutic target. Drugs that would improve Kv4.3 mediated K⁺ current, for instance by blocking the channel in the open state, could be of therapeutic benefit for the treatment of arrhythmic heart failure and other diseases related to interruptions in smooth muscle action potential.

Kv4.3 and other valuable molecular drug targets such as ion channels, vesicular transporters and synaptic proteins require a complex physiological environment to function. For example, assessment of the gating properties of compounds on ion channels at high throughput remains an industry challenge, particularly for voltage gated ion channels. Some ion channel drugs interact only with a specific conformation of the protein molecule and block the channel either in the open or in the closed configuration. Such 'smart' drugs can only be identified in a functional screen.

The pharynx of C. elegans is a validated model system for neuronal signalling and membrane excitability. For example, the voltage-gated K⁺ channels EXP-2 in C. elegans influences the shape and duration of the pharyngeal muscle action potential. Loss-of-function mutations in this voltage-gated K⁺ channel lead to delayed repolarization and reduced frequency of pharyngeal muscle action potentials.

The relevant physiology of C. elegans offers the opportunity to study ion channels and other "tough" transmembrane targets in an in vivo environment. Devgen has developed standardized C. elegans assays that enable these targets to be screened at relatively high throughput (up to 9K compounds per week) in homogeneous assays using £30 micromolar compound. The potential of this technology will be illustrated by presenting data generated during assay development and HTS of the human KV4.3 channel in C. elegans.