Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Abstract

The K V 1.3 voltage‐gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K V 1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K V 1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K V 1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward K V 1.3. Selectivity of dalatazide (ShK‐186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small‐molecule inhibitors are critically evaluated for their lead‐like characteristics and potential for progression into clinical development. Some small‐molecule inhibitors with well‐defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K V 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K V 1.3 modulators against this target in the future.

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.…”

Bioengineered System for High Throughput Screening of Kv1 Ion Channel Blockers

“…Notably, a number of bioactive small molecules (such as 4-aminopiridine, clofazimine and psoralenic compounds) inhibit Kv1 channels from the inside of the cell [17], thus preventing implementation of a competitive binding assay using Kv1-KcsA hybrids. Consequently, our flow cytometry approach can be used to screen unlabeled small organic blockers for their binding with the external lining of the pore.…”

“…These results are expected since toxin (M r = 4-5 kDa) labeling with a large fluorescent protein (M r = 26 kDa) is likely to compromise its binding. AgTx2 and ChTx have different binding sites on the Kv1.3 channel pore [17]. Thus, we have measured the apparent dissociation constant of ChTx by its ability to displace either ChTx-GFP or AgTx2-GFP.…”

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

“…In fact, one characteristic of activated inflammatory cells is an increased expression and function of the K V 1.3 channels ( Pérez-Verdaguer et al, 2016 ). In quiescent cells K V 1.5 regulates the proliferation rate ( Pannasch et al, 2006 ; Gubiè et al, 2021 ) while K V 1.3 is dominant in activated microglial cells ( Gubiè et al, 2021 ). Besides, K V 1.5 seems to be essential for NO production ( Pannasch et al, 2006 ), but causes cell cycle arrest.…”