Publication Date
8-14-2020
Journal
ACS Pharmacology & Translational Science Journal
DOI
10.1021/acsptsci.0c00035
PMID
32832873
PMCID
PMC7432667
PubMedCentral® Posted Date
5-14-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
KV1.3, potassium channel, plant defensin, cell-penetrating peptide, peptide therapeutic, effector memory T cell, rheumatoid arthritis, autoimmune disease, grapevine, oil palm
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. 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.
Graphical Abstract
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