Ion Channel Screening

Abstract

Ion channels are attractive targets for drug discovery with recent estimates indicating that voltage and ligand-gated channels account for the third and fourth largest gene families represented in company portfolios after the G protein coupled and nuclear hormone receptor families. A historical limitation on ion channel targeted drug discovery in the form of the extremely low throughput nature of the gold standard assay for assessing functional activity, patch clamp electrophysiology in mammalian cells, has been overcome by the implementation of multi-well plate format cell-based screening strategies for ion channels. These have taken advantage of various approaches to monitor ion flux or membrane potential using radioactive, non-radioactive, spectroscopic and fluorescence measurements and have significantly impacted both high-throughput screening and lead optimization efforts. In addition, major advances have been made in the development of automated electrophysiological platforms to increase capacity for cell-based screening using formats aimed at recapitulating the gold standard assay. This review addresses the options available for cell-based screening of ion channels with examples of their utility and presents case studies on the successful implementation of high-throughput screening campaigns for a ligand-gated ion channel using a fluorescent calcium indicator, and a voltage-gated ion channel using a fluorescent membrane potential sensitive dye.

Extracellular Ion Channel Inhibitor Antibodies

“…Many current drug development programmes are based on screening vast chemical libraries using high throughput systems [4,5]. Unfortunately, the costs and timecommitments for such screens are high, making early validation of targets by other means a valuable step.…”

CHAPTER 4. Venoms-Based Drug Discovery: Bioassays, Electrophysiology, High-Throughput Screens and Target Identification

“…In addition, commercially available automated electrophysiology platforms, such as the OpusXpress (Axon Instruments) and Robocyte/HiClamp (MultiChannel Systems GmbH) for oocyte recording, and PatchXpress (Axon Instruments), Patchliner (Nanion Technologies GmbH), IonWorks Barracuda and Quattro (Molecular Devices), QPatch (Sophion) and Flyscreen 8500 (Flyion GmbH) for isolated cell recording, have increased throughput. [104][105][106][107] However, most systems still cannot rival plate-based, high-throughput screening assays. The advantages of these automated electrophysiology platforms, which can assay eight, 16 or more cells in parallel, have oen come at the expense of assay exibility and signicant cost.…”

Venom Peptides as a Rich Source of Cav2.2 Channel Blockers

“…A range of HTS assays to screen new Ca v 2.2 channel inhibitors have been described, including fluorescence-based Ca 2+ assays and radioligand binding assays [124,144,145,146,147]. Radioligand binding assays are amenable to HTS, however, these assays cannot detect modulators acting at different sites from the ω-conotoxin site on Ca v 2.2.…”