Achieving small molecule selectivity for ion channels can be challenging; therefore, peptide toxins have sparked considerable interest to advance both basic research and scaffold-based drug discovery. However, efficient isolation of the correctly folded peptide at a low cost is a current limitation. Recombinant expression of toxin peptides fused to a scaffold protein is an emerging strategy to overcome these production challenges, as well as enhancing in vivo stability of the toxin peptide.
Using automated patch clamp technology, we evaluate the potency and selectivity of ten NaV1.7-selective arachnid peptide toxins, which have been fused to the C-terminus (Fc region) of human IgG1.
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Optical voltage imaging of human iPSC-derived cardiomyocytes was used to assess electrophysiological effects of compounds beyond hERG inhibition. Action potential waveform analysis revealed compound-specific and concentration-dependent changes, enabling mechanistic differentiation of multichannel activity and demonstrating a human-relevant approach for translational cardiac safety assessment.
The presence of sensory neuron markers, excitability properties consistent with sensory neurons, and evidence of nociceptor ion channels (using both RNASeq and electrophysiology) provides strong evidence that iCell Sensory Neurons have a robust sensory neuron phenotype suitable for supporting pain discovery programs.