Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds

Area of Science:

• Pharmacology
• Cardiovascular Physiology
• Biophysics

Background:

• Drug-induced arrhythmias, specifically torsades de pointes, are often caused by unintended inhibition of the cardiac potassium channel human ether-a-go-go-related gene (hERG).
• Traditional electrophysiology is reliable for identifying hERG liabilities but lacks the throughput for extensive drug discovery programs.
• Recent advancements in planar electrode-based voltage clamp electrophysiology offer a potential solution for high-throughput screening.

Purpose of the Study:

• To assess the reliability of planar electrode voltage clamp electrophysiology for measuring small molecule activity on the hERG channel.
• To compare the performance of this new technology with traditional glass micropipette-based electrophysiology.
• To determine if the new technology can support the throughput needs of drug discovery.

Main Methods:

• Utilized the Sealchip and PatchXpress technology platform (AVIVA Biosciences Corp.) for planar electrode electrophysiology.
• Screened a panel of well-characterized molecules known to be active or inactive at the hERG channel.
• Compared results with traditional glass micropipette-based electrophysiology methods.

Main Results:

• Demonstrated that planar electrode electrophysiology is comparable to traditional methods in reliability and data content for hERG channel activity.
• Showcased the ability of the Sealchip and PatchXpress platform to accurately measure hERG channel inhibition by small molecules.
• Confirmed the high-throughput potential of planar electrode technology.

Conclusions:

• Planar electrode electrophysiology, using the Sealchip and PatchXpress platform, is a reliable and effective method for assessing hERG channel activity.
• This technology offers significantly higher throughput, enabling more comprehensive testing of pharmaceutical compounds.
• The adoption of this method can enhance early-stage drug safety evaluations and support drug discovery programs.