Abstract

Voltage gated sodium (NaV1.X) channels have been extensively studied as therapeutic targets for indications such as pain, epilepsy and paralysis. However, small molecule interventions have largely failed in the clinic due to challenges in developing modulators with high subtype selectivity, required to minimize off-target effects. Many animal venoms have evolved as highly potent, selective and stable modulators of NaV1.X channels in order to defend against predators and subdue prey. Thus, toxins extracted from animal venoms may provide novel starting material for future drug discovery campaigns.
In a collaboration between Charles River and Venomtech, we have extracted, fractionated and standardized venoms from 17 Theraphosidae species to create a Targeted-Venom Discovery Array. 960 fractions were screened in single point format against NaV1.4 and NaV1.7 channels using the Sophion Qube high-throughput automated patch clamp platform. Active fractions were retested as concentration-response curves, and the most promising hits were progressed to Mass Spectrometry hit identification.
In this joint presentation, we share our insight into developing a library of venom fractions using in-line 2D HPLC and screening using automated patch clamp technology, concluding with a discussion on the potential of using animal venoms as new therapeutic modalities.