中文
First published: June 2, 2020
We have recently published a joint collaboration paper with our long time collaborators: K. George Chandy, Ray S. Norton, Christine Beeton and Heike Wulff in the prestigious journal ACS Pharmacology and Translational Science. This newest report describes a novel group of cell-penetrating disulfide-rich defensin peptides isolated from plants such as grapes and palms. These defensin peptides penetrate the cell membrane of T-cells and affect the Kv1.3 channel via a novel mechanism of action. Crystal structural data along with solution NMR structures are also used to further characterize these peptide showing structural homology to the scorpion venom peptide, kaliotoxin. To view the full article, please click the following link: https://pubs.acs.org/doi/pdf/10.1021/acsptsci.0c00035
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 rundown 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 at 10-100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.