Modulation of lymphocyte potassium channel KV1.3 by membrane penetrating, joint targeting immunomodulatory plant defensin

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 amongst 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 dermatitis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed …