Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin


ACS Pharmacology & Transitional Science


Seow Theng Ong,* Saumya Bajaj, Mark R. Tanner, Shih Chieh Chang, Bankala Krishnarjuna, Xuan Rui Ng, Rodrigo A. V. Morales, Ming Wei Chen, Dahai Luo, Dharmeshkumar Patel, Sabina Yasmin, Jeremy Jun Heng Ng, Zhong Zhuang, Hai M. Nguyen, Abbas El Sahili, Julien Lescar, Rahul Patil, Susan A. Charman, Edward G. Robins, Julian L. Goggi, Peng Wen Tan, Pragalath Sadasivam, Boominathan Ramasamy, Siddana V. Hartimath, Vikas Dhawan, Janna Bednenko, Paul Colussi, Heike Wulff, Michael W. Pennington, Serdar Kuyucak, Raymond S. Norton, Christine Beeton, and K. George Chandy*



We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T-lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10–100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

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