Arthur Brown, M.D., Ph.D., president and CEO of ChanTest, summed up the sentiments of a number of speakers at the recent “SBS Conference” in Lille, France, when he said, “Ion channels are as abundant as GPCRs in the known druggable genome and have as much potential as drug targets for pain, hypertension, and inflammation. Yet they still don’t receive the time and attention they should from drug developers.”
Kim Dekermendjian, Ph.D., senior research scientist in molecular pharmacology at AstraZeneca, agreed, adding “only seven percent of current drug targets are ion channels while 30 percent are GPCRs, so ion channels are totally underexploited and this is because historically it has been so difficult to screen them in a rational way.”
Since ion channels are a diverse family of pore-forming proteins that control the voltage gradient and ionic flow across the plasma membrane, it is well established that the most accurate method of measuring a drug’s effects on an ion channel is via patch clamping.
This works by forming a patch through which intracellular access is gained to measure and control membrane voltage and current flowing through the cell membrane. In the past five years relatively low-throughput automated patch clamps such as the QPatch from Sophion Bioscience, the Patchliner from Nanion Technologies, and the PatchXpress® and IonWorks® Quattro™ systems from Molecular Devices, a MDS Analytical company, have emerged. The cost per data point, however, has made these automated methods too expensive to use in primary screening.
According to Dr. Dekermendjian, sometimes the screening costs of using these systems, even in secondary screens, is referred to at AstraZeneca as “tears per data point”. As a result, surrogate measures of ion-channel activity such as ligand displacement, ionic flux, and membrane potential are used as primary screens with equipment including the Molecular Devices FLIPRTetra®, the most commonly used.
The disadvantage of using these assays is they cannot maintain a population of ion channels in a particular conformational state due to the lack of voltage control and so need to be used as methods to weed out the best drug candidates for a confirmatory patch-clamp screen. “The surrogate measures are nonfunctional and cannot identify allosteric modulators,” noted Dr. Brown. “Ion-channel sites for allosteric modulators are enormous and relatively untapped.”