Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Abstract

It remains a challenge for the effective treatment of neuroinflammatory disease, including multiple sclerosis (MS), stroke, epilepsy, and Alzheimer's and Parkinson's disease. The voltage-gated potassium Kv1.3 channel is of interest, which is considered as a novel therapeutic target for treating neuroinflammatory disorders due to its crucial role in subsets of T lymphocytes as well as microglial cells. Toxic animals, such as sea anemones, scorpions, spiders, snakes, and cone snails, can produce a variety of toxins that act on the Kv1.3 channel. The Stichodactyla helianthus K⁺ channel blocking toxin (ShK) from the sea anemone S. helianthus is proved as a classical blocker of Kv1.3. One of the synthetic analogs ShK-186, being developed as a therapeutic for autoimmune diseases, has successfully completed first-in-man Phase 1 trials. In addition to addressing the recent progress on the studies underlying the pharmacological characterizations of ShK on MS, the review will also explore the possibility for clinical treatment of ShK-like Kv1.3 blocking polypeptides on other neuroinflammatory diseases.

Keywords: Alzheimer’s disease; Kv1.3; Parkinson’s disease; ShK; epilepsy; multiple sclerosis; neuroinflammatory disease; stroke.

FIGURE 1

The structures of Kv1.3 blocking toxin peptides. (A) The sea anemone toxin ShK (PDB: 1ROO) is isolated and purified from Sidirodromi hellinikou. The scorpion toxins BmP02 (PDB: 1DU9), BmKTX (PDB: 1BKT), and scorpion defensin BmKDfsin4 (using micasin as a template, PDB: 2LR5) are isolated and purified from Mesobuthus martensii. The scorpion toxin ChTX (PDB: 2CRD) is isolated and purified from Leiurus quinquestriatus. The scorpion toxin OSK1 (PDB: 1SCO) is isolated and purified from Orthochirus scrobiculosus. The scorpion toxin KTX (PDB: 2KTX) is isolated and purified from Androctonus mauritanicus. The three-dimensional structure data of the toxin polypeptide in the figure refers to the PDB. (B) Multiple sequence alignment of ShK and ShK-like Kv1.3 blockers from sea anemone or scorpion venom. Conserved cysteines formatting intrachain disulfide bonds are in red and shadowed in yellow; residues conserved in most of the peptides are shadowed in blue; residues with same charge in most of the peptides are shadowed in green. The species of toxins acting on Kv1.3 are mentioned above, except for Tc32 isolated from Tityus cambridgei; Pi1 isolated from Pandinus imperator; Kaliotoxin isolated from Androctonus mauritanicus; margatoxin isolated from Centruroides margaritatus; noxiustoxin isolated from Centruroides noxius. (C) A guide tree is constructed by ALIGNX, a component of the VECTOR NTI 11.0 software suite. Scores in the brackets are based on the identity of the amino acids chemical properties.

FIGURE 2

ShK and Kv1.3 blocking polypeptides as potential therapeutic agents for neuroinflammatory diseases. ShK and Kv1.3 toxins might be used to treat multiple sclerosis, and other neuroinflammatory disorders via inhibiting Kv1.3 expressed in T lymphocytes as well as microglial cells.