| Literature DB >> 32832873 |
Seow Theng Ong1, Saumya Bajaj1, Mark R Tanner2, Shih Chieh Chang1, Bankala Krishnarjuna3, Xuan Rui Ng1, Rodrigo A V Morales3, Ming Wei Chen1, Dahai Luo1, Dharmeshkumar Patel4, Sabina Yasmin4, Jeremy Jun Heng Ng1, Zhong Zhuang1, Hai M Nguyen5, Abbas El Sahili6, Julien Lescar6, Rahul Patil7, Susan A Charman7, Edward G Robins8,9, Julian L Goggi8, Peng Wen Tan8, Pragalath Sadasivam8, Boominathan Ramasamy8, Siddana V Hartimath8, Vikas Dhawan10,11, Janna Bednenko12, Paul Colussi12, Heike Wulff5, Michael W Pennington10,11, Serdar Kuyucak4, Raymond S Norton3,13, Christine Beeton2, K George Chandy1.
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.Entities:
Year: 2020 PMID： 32832873 PMCID： PMC7432667 DOI： 10.1021/acsptsci.0c00035
Source DB: PubMed Journal: ACS Pharmacol Transl Sci ISSN： 2575-9108