20.500.12556/RUL-144768 Discovery of K$_V$1.3 ion channel inhibitors medicinal chemistry approaches and challenges The K$_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$1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no KV1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K$_V$1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward KV1.3. Selectivity of dalatazide (ShK‐186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small‐molecule inhibitors are critically evaluated for their lead‐like characteristics and potential for progression into clinical development. Some small‐molecule inhibitors with well‐defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K$_V$1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K$_V$1.3 modulators against this target in the future. K$_V$1.3 channel design of K$_V$1.3 inhibitors mitochondrial K$_V$1.3 peptide inhibitors small-molecule inhibitors farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2023-03-10 15:06:56 2023-03-10 15:07:00 2023-03-11 03:36:50 0000-00-00 00:00:00 2021 0 0 Str. 2423-2473 iss. 4 Vol. 41 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1098-1128 10.1002/med.21800 61605123 Medicinal_Research_Reviews_-_2021_-_Gubi_-_Discovery_of_KV1_3_ion_ch.pdf Medicinal_Research_Reviews_-_2021_-_Gubi_-_Discovery_of_KV1_3_ion_ch.pdf 1 6450AEB31CA8F06283C18E57E2B12BF1 f5cf5bb126ddeea9e11946ca764712d1fd008bcff8fc74e9d0dabe1237ccb188 122a991b-bf4d-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167273 https://onlinelibrary.wiley.com/doi/10.1002/med.21800 0 f008593a-bf4c-11ed-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=167272 Fakulteta za farmacijo 0 0 0