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Jun 1, 2009 (Vol. 29, No. 11)

Investigating and Focusing on Ion Channels as Drug Targets

New Screening Methods Could Increase the Utility of These Abundant Proteins

  • When Patch Clamping Won't Work

    Click Image To Enlarge +
    IonGate Biosciences’ SURFE2R Workstation 5000 doesn’t use whole cells but instead reads the charge-displacement from membrane preparations isolated from cell culture.

    “Although patch clamping is the standard for measuring ion channels, there are some ion-conducting proteins that it simply cannot be used for,” explained Petr Obrdlik, Ph.D., head of assay development at IonGate Biosciences. “You cannot measure the effects of drugs on the native intracellular organelles because standard patch-clamping equipment cannot access these membranes. I have never seen any publications on patch clamping of respiratory chain complexes and oxidative phosphorylation, for example, so these are valid yet hidden targets for many potential drugs.”

    To overcome this problem, IonGate has developed SURFE2R (surface electrogenic event reader) technology that doesn’t use whole cells, but instead, reads the charge displacement from membrane preparations isolated from cell culture. The membranes are coupled via an alkaline thiol and lipid bilayer to gold-coated electrodes, and it is the electrode that detects changes in the electrical signal without the need to use reporter molecules. Beside mitochondrial membranes, the technique is also suited for native membranes from different tissues and different species such as transport proteins of heart plasma membranes, synaptic vesicles, and sarcoplasmic reticulum.   

    At the “SBS” meeting, an interesting application of the SURFE2R was presented by Victoria Balannik, Ph.D., of Northwestern University. Dr. Balannik showed that, by using the system, it was possible to measure the activity of the anti-influenza drug amantadine on the M2 ion channel protein from influenza A. “It is extremely difficult and time consuming to perform high-throughput screening of the activity of novel anti-viral agents on M2 by conventional electrophysiology,” Dr. Balannik said.

    “This technology is complementary to patch clamping,” Stefan Schork, vp of sales at IonGate, concluded. “Since it is now available in a higher throughput format as the SURFE2R Workstation 5000, it will open up the possibility of screening drugs that target transporters and channels in their native sub-cellular surroundings.”

  • Bright Future?

    New high-throughput screening technologies being introduced could make working on ion-channel targets more attractive. According to Dr. Dekermendjian, the ideal scenario would be able to screen 100,000 data points per day at a cost of $0.10 per data point so it is clear that many of the high-throughput electrophysiology systems shown at the “SBS Conference” are still around an order of magnitude away in terms of throughput and cost. As there have been such vast improvements in both throughput and cost in the past three years it cannot be long before high-throughput patch clamping for primary screening becomes a reality.

    With the improvement in automated patch-clamping methods, however, comes the difficulty of finding appropriate cell lines to use in the screens. Companies such as ChanTest and Genionics with its offering of around 30 ChanClone™ ion-channel cell lines, as well as larger players like PerkinElmer, which introduced new ion-channel expressing cell lines at the conference, are beginning to recognize this gap.

    Andrew Southan, director of ion-channel biology at BioFocus DPI, feels there is still something missing. “If we are going to use automated patch clamping as a primary screening tool then, in addition to clonal cell lines, we should also seek to incorporate more physiological models such as immortalized cell lines from disease-related tissue and stem cells.

    “This approach would clearly include experimental challenges to reduce off-target background currents, but undoubtedly creates an opportunity for pharmaceutical researchers and stem cell manufacturers to seriously consider the development of robust lines which work well on automated patch-clamp systems.”

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