7c2p

Publication Abstract from PubMed

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 (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.

Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.,Ong ST, Bajaj S, Tanner MR, Chang SC, Krishnarjuna B, Ng XR, Morales RAV, Chen MW, Luo D, Patel D, Yasmin S, Ng JJH, Zhuang Z, Nguyen HM, El Sahili A, Lescar J, Patil R, Charman SA, Robins EG, Goggi JL, Tan PW, Sadasivam P, Ramasamy B, Hartimath SV, Dhawan V, Bednenko J, Colussi P, Wulff H, Pennington MW, Kuyucak S, Norton RS, Beeton C, Chandy KG ACS Pharmacol Transl Sci. 2020 May 14;3(4):720-736. doi:, 10.1021/acsptsci.0c00035. eCollection 2020 Aug 14. PMID:32832873^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.