The Kv1.3 K+ channel in the immune system and its “precision pharmacology” using peptide toxins

Since the discovery of the Kv1.3 voltage-gated K+ channel in human T cells in 1984, ion channels are considered crucial elements of the signal transduction machinery in the immune system. Our knowledge about Kv1.3 and its inhibitors is outstanding, motivated by their potential application in autoimmune diseases mediated by Kv1.3 overexpressing effector memory T cells (e.g., Multiple Sclerosis). High affinity Kv1.3 inhibitors are either small organic molecules (e.g., Pap-1) or peptides isolated from venomous animals. To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24. These peptides inhibit Kv1.3 in picomolar concentrations and are several thousand-fold selective for Kv1.3 over other biologically critical ion channels. Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition