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Jun 15, 2010 (Vol. 30, No. 12)

Ion Channels Open Doors to New Drugs

Increased R&D Efforts Are Overcoming Obstacles and Showing Potential

  • Ion channels make good drug targets—they reside on the cell surface and are fast switching mechanisms. They act like cell transistors, controlling many cell processes. There are close to 500 types of ion channels, yet many remain undiscovered. This was mainly attributed to technology restraints, however, with the recent introduction of HT patch clamping, as well as new assays that facilitate faster, more robust screening, there are more ion channel receptors being detected.

    Researchers at the recent Society for Biomolecular Screening conference and CHI’s upcoming “Pharmacology Driven Assays for GPCRs and Ion Channels” shared information on a cornucopia of topics, including the latest enabling technologies, new screening paradigms, and novel approaches to generate GPCRs.

    The IonFlux system from Fluxion Biosciences was recently beta tested by scientists at Novartis Institutes for Biomedical Research (NIBR). “Compounds, buffers, and waste are contained on a single 96-well plate, eliminating robotic handling. Air pressure drives experiments in microfluidic channels in a layer below the wells. This is a novel approach in automated electrophysiology,” explained Andrew Golden, Ph.D., post-doc fellow.

    Robustness is enhanced via recordings taken from 20-cell ensembles (IonFlux HT), and pharmacology improved by recording a full range of concentrations from the same group of cells, according to the company. There are two available systems—the IonFlux 16, which uses 96-well plates, and the IonFlux HT, which uses 384-well plates.

    Analysis of the prototype (alpha and beta testing) was initially focused on whether IonFlux could reproduce results demonstrated on other platforms. “The microfluidic approach could be helpful for ligand-gated ion channels—especially for subsets of those for fast desensitizing ligand-gated ion channels where you only add a short pulse of the ligand or neurotransmitter,” explained Mats Holmqvist, Ph.D., research investigator in the center for proteomic chemistry at NIBR.

    In addition, Dr. Holmqvist said the hope for the new platform is that it should provide selectivity not only by target but also by function. “You can utilize ‘use dependency’—the accumulation of inhibition with repetitive depolarizations. If an ion channel is active, the drug may be much more potent.” With this new technology, one should be able to refine and understand how a compound affects an ion channel. However, it’s still too early to show whether this will be the case.

    Since HT platforms for ion channels are fairly new, standardization across different instruments hasn’t been addressed. “There are different quality control parameters, including the way of recording a single cell per well or ensemble recording in parallel. Some machines use Oracle database versus file formats. We’ve been trying to address that in safety profiling. A quick answer is that we make a summary PDF file of every compound in each experiment that can be accessed any time,” noted Dr. Holmqvist.

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