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<p>Autoimmune diseases (ADs) affect almost 10% of the world population. They are also the leading cause of mortality among young and middle-aged women. Despite the available of therapeutic agents there is no definitive cure. The voltage-gated potassium channel (Kv1.3) plays a key role regulating various physiological processes, particularly immune responses, making it a promising target for immunomodulators. Moreover, the ability of Kv1.3 blockers to selectively modulate the activation of effector memory T-cells, without affecting other lymphoid subsets, make it a promising target to avoid fatal opportunistic infections encountered with broad spectrum immunosuppressants. Herein, a β-carboline-based lead (<b>KMA</b>) was developed through ligand-directed scaffold hopping based on the known Kv1.3 inhibitors, pyranoquinolinone and CP-339,818. Iterative structural derivatization and scaffold hopping produced piperidine and the hybrid analogs based on scaffolds of the potent Kv1.3 small inhibitors, UK-78,282 and PAP-1. Our biological assays produced two promising compounds; β-carboline-based (<b>5c</b>) and hybrid (<b>13a</b>). Notably, the hybrid compound <b>13a</b> showed promising activity in relation to the <i>Centruroides margaritatus</i> scorpion short-chain toxin, margatoxin, which was used as positive control standard. Only compound <b>13a</b> managed to decrease the Kv1.3 peak current amplitude by more than 80%, suggesting its viability as a lead compound for further investigations targeting ADs.</p>

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Design and synthesis of novel small molecules targeting the Kv1.3 voltage-gated potassium ion channel

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月24日

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  • Ahmad Abdelwaly,
  • Mohamed A. Helal,
  • Marwa M. Fathy,
  • Hamdy Alaaeldeen,
  • Michael L. Klein,
  • Khaled M. Darwish

摘要

Autoimmune diseases (ADs) affect almost 10% of the world population. They are also the leading cause of mortality among young and middle-aged women. Despite the available of therapeutic agents there is no definitive cure. The voltage-gated potassium channel (Kv1.3) plays a key role regulating various physiological processes, particularly immune responses, making it a promising target for immunomodulators. Moreover, the ability of Kv1.3 blockers to selectively modulate the activation of effector memory T-cells, without affecting other lymphoid subsets, make it a promising target to avoid fatal opportunistic infections encountered with broad spectrum immunosuppressants. Herein, a β-carboline-based lead (KMA) was developed through ligand-directed scaffold hopping based on the known Kv1.3 inhibitors, pyranoquinolinone and CP-339,818. Iterative structural derivatization and scaffold hopping produced piperidine and the hybrid analogs based on scaffolds of the potent Kv1.3 small inhibitors, UK-78,282 and PAP-1. Our biological assays produced two promising compounds; β-carboline-based (5c) and hybrid (13a). Notably, the hybrid compound 13a showed promising activity in relation to the Centruroides margaritatus scorpion short-chain toxin, margatoxin, which was used as positive control standard. Only compound 13a managed to decrease the Kv1.3 peak current amplitude by more than 80%, suggesting its viability as a lead compound for further investigations targeting ADs.