Discovery of K$_V$1.3 ion channel inhibitors : medicinal chemistry approaches and challenges

Gubič, Špela (author), Hendrickx, Louise Antonia (author), Toplak, Žan (author), Sterle, Maša (author), Peigneur, Steve (author), Tomašič, Tihomir (author), Pardo, Luis A. (author), Tytgat, Jan (author), Zega, Anamarija (author), Peterlin-Mašič, Lucija (author)

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.

• Language: English
• Keywords: K$_V$1.3 channel, design of K$_V$1.3 inhibitors, mitochondrial K$_V$1.3, peptide inhibitors, small-molecule inhibitors
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: Str. 2423-2473
• Numbering: Vol. 41, iss. 4
• PID: 20.500.12556/RUL-144768
• UDC: 615.4:54
• ISSN on article: 1098-1128
• DOI: 10.1002/med.21800
• COBISS.SI-ID: 61605123
• Publication date in RUL: 10.03.2023

Record is a part of a journal

• Title: Medicinal research reviews
• Shortened title: Med. res. rev.
• Publisher: Wiley
• ISSN: 1098-1128
• COBISS.SI-ID: 512824089

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: farmacevtska kemija