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

ST Ong; S Bajaj; MR Tanner; SC Chang; B Krishnarjuna; XR Ng; RAV Morales; MW Chen; D Luo; D Patel; S Yasmin; JJH Ng; Z Zhuang; HM Nguyen; A El Sahili; J Lescar; R Patil; SA Charman; EG Robins; JL Goggi; PW Tan; P Sadasivam; B Ramasamy; SV Hartimath; V Dhawan; J Bednenko; P Colussi; H Wulff; MW Pennington; S Kuyucak; RS Norton; C Beeton; KG Chandy

Journal article

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

ST Ong, S Bajaj, MR Tanner, SC Chang, B Krishnarjuna, XR Ng, RAV Morales, MW Chen, D Luo, D Patel, S Yasmin, JJH Ng, Z Zhuang, HM Nguyen, A El Sahili, J Lescar, R Patil, SA Charman, EG Robins, JL Goggi Show all

ACS Pharmacology and Translational Science | American Chemical Society (ACS) | Published : 2020

DOI: 10.1021/acsptsci.0c00035

Open access

Abstract

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...

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