The voltage-gated potassium channel Kv1.3 in T lymphocytes is a validated therapeutic target for diverse autoimmune diseases.1 Peptide inhibitors of the channel have proven to particularly effective,2 and indeed the first Kv1.3-selective inhibitor in human trials is a peptide derived from a venomous marine organism.3 Two broad classes of peptides are potent blockers of Kv1.3, the first from scorpions and the second from sea anemones.2
This presentation will describe the properties of a potent and selective inhibitor of Kv1.3, HsTX1[R14A],4 which was developed from a peptide identified in scorpion venom. This 34-residue peptide is straightforward to synthesize and fold, despite having four disulfide bonds, and is highly resistant to proteolysis. It has proven to be effective in animal models of autoimmune diseases such as rheumatoid arthritis,5 where its effective (pharmacodynamic) half-life vastly exceeds its half-life in the circulation. PET imaging data show that it accumulates in kidneys,6 making it particularly attractive as a therapeutic for autoimmune diseases of the kidney, such as glomerular nephritis.
There is also evidence for Kv1.3 involvement in neuroinflammatory conditions such as Alzheimer’s and Parkinson’s diseases.7 We are therefore exploring ways of delivering this peptide to the CNS as a potential therapeutic intervention.
1 Chandy, K. G. & Norton, R. S. Curr. Opin. Chem. Biol. 38, 97-107 (2017).
2 Norton, R. S. & Chandy, K. G. Neuropharmacology 127, 124-138 (2017).
3 Tarcha, E. J. et al. PloS one 12, e0180762 (2017).
4 Rashid, M. H. et al. Sci Rep 4, 4509 (2014).
5 Tanner, M. R. et al. Clin. Immunol. 180, 45-57 (2017).
6 Bergmann, R. et al. Sci Rep 7, 3756 (2017).
7 Di Lucente, J., Nguyen, H. M., Wulff, H., Jin, L. W. & Maezawa, I. Glia 66, 1881-1895 (2018).