Poster
19

Toxin pharmacology and MoA data against Nav1.X channels: Multi-parameter analysis using Sophion Qube high-throughput automated patch clamp platform

Authors

E Duncan1; S Williams1; J Kammonen1
1 Charles River Discovery, UK

Abstract

Objective

Voltage-gated sodium (NaV) channels have been extensively studied as targets for therapeutic indications such as pain, epilepsy and paralysis. However, small molecule interventions have been largely unsuccessful in the clinic, primarily due to challenges in developing compounds with high subtype selectivity to minimise off-target effects. Many animal venoms have evolved as potent NaV channel modulators with high specificity to individual subtypes, and as a result, toxins have been increasingly used in the development of novel therapeutics.


Traditionally, ion channels have been challenging to study in drug development due to laborious manual patch clamp approaches. However, recent advances in high-throughput automated patch clamp (APC) technologies have allowed high quantities of meaningful data to be generated quickly.


Methods

The adaptive voltage protocol on the Sophion Qube 384-well APC platform allows Boltzmann fits and V1/2 values to be calculated and applied to individual wells. Here, we use this protocol to complete multi-parameter analysis of toxin pharmacology on NaV1.7 and NaV1.8 channels.


Results

A selection of toxins and small molecules with known NaV1.7 or 1.8 modulating properties were profiled and hit finding strategies are demonstrated for identifying compounds with specific mechanisms of action direct from single point screening. Modulators with state-dependence and differences in channel kinetics can be recognised from single well data, and potency values generated are in line with published literature.


Conclusion

The adaptive voltage protocol on the Sophion Qube has been used to successfully generate pharmacology for a range of small molecules and toxins. All data presented was obtained from a single Qube experiment for each cell line tested, demonstrating the high quantity and quality of meaningful data which can be obtained using automated patch clamp technology.


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