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

Abstract

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.

Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

“…In addition, there are other methods and techniques for increasing the affinity and selectivity of a peptide. For example: acidic-residue-function-guided drug design; chemical modification; residue truncation; binding interface modulation; reducing conformational flexibility; scaffold-/target-biased strategies; Artificial Intelligence-guided drug design [136][137][138].The overall methodological background and information on the interaction between toxins and Kv channels allows us to work with toxins, such as Osu1 and Ts6, generating and testing analogs until the toxin with the best affinity and selectivity is found, or to find analogs of other toxins related to Osu1 or Ts6 that may have similar activity on the Kv1.5 channel.…”

Purification and Characterization of Bot33: A Non-Toxic Peptide from the Venom of Buthus occitanus tunetanus Scorpion

“…Many K + channel toxin inhibitors contain a critical positive charged residue (Lys or Arg) that protrudes into the channel pore and interacts with a Tyr residue situated in the selectivity filter of the K + channel [ 27 , 28 , 29 , 30 ]. On the other hand, a hydrophobic residue (Tyr, Phe, Leu), contributes to the selectivity profile among different KV1.x channels [ 15 , 31 , 32 ]. Thus, this hydrophobic residue, with Lys 27 separated by a distance of 6.6 A, constitutes a functional dyad, reported to be essential for the high affinity toward Kv1.x channels.…”

GFP–Margatoxin, a Genetically Encoded Fluorescent Ligand to Probe Affinity of Kv1.3 Channel Blockers

“…Functionally, these peptides are Kv1.3 channel blockers, which interact with the external vestibule of the channel occluding the ion-conducting pathway of the pore domain [2]. Inhibiting Kv1.3 channels by peptide blockers results in pronounced physiological effects, providing an opportunity to design peptide-based drugs with high selectivity and low off-target effects [4]. Thus, a demand for peptide blockers with biased selectivity towards the target channel guides the ongoing studies of peptide toxins from the natural sources, as well as further characterization of their binding activities.…”