1. Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin
- Author
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Raymond S. Norton, Michael W. Pennington, Paul A. Colussi, Pragalath Sadasivam, Peng Wen Tan, Serdar Kuyucak, Zhong Zhuang, Bankala Krishnarjuna, Abbas El Sahili, Sabina Yasmin, Xuan Rui Ng, Rahul Patil, Christine Beeton, Edward G. Robins, Saumya Bajaj, Mark R. Tanner, Vikas Dhawan, Dahai Luo, Ming Wei Chen, Dharmeshkumar Patel, Hai M. Nguyen, Julien Lescar, Jeremy Jun Heng Ng, Heike Wulff, Rodrigo A.V. Morales, Boominathan Ramasamy, Julian L. Goggi, Janna Bednenko, Shih Chieh Chang, Seow Theng Ong, Siddana V. Hartimath, K. George Chandy, and Susan A. Charman
- Subjects
Pharmacology ,Autoimmune disease ,Effector ,Lymphocyte ,medicine.disease ,Potassium channel ,Cell biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,In vivo ,medicine ,Cell-penetrating peptide ,Pharmacology (medical) ,Phosphatidylinositol ,Receptor - Abstract
[Image: see text] We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K(V)1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K(V)1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K(V)1.3 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 (18)F-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.
- Published
- 2020