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.
Development of a robust hNaV1.9 high-throughput screening assay on the Sophion Qube384 platform. This is complemented by a suite of ion channel selectivity assays and sensory neuron recordings to create a versatile screening cascade to support NaV1.9 drug discovery programmes.
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.