TY - JOUR
T1 - Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin
AU - Ong, Seow Theng
AU - Bajaj, Saumya
AU - Tanner, Mark R.
AU - Chang, Shih Chieh
AU - Krishnarjuna, Bankala
AU - Ng, Xuan Rui
AU - Morales, Rodrigo A.V.
AU - Chen, Ming Wei
AU - Luo, Dahai
AU - Patel, Dharmeshkumar
AU - Yasmin, Sabina
AU - Ng, Jeremy Jun Heng
AU - Zhuang, Zhong
AU - Nguyen, Hai M.
AU - El Sahili, Abbas
AU - Lescar, Julien
AU - Patil, Rahul
AU - Charman, Susan A.
AU - Robins, Edward G.
AU - Goggi, Julian L.
AU - Tan, Peng Wen
AU - Sadasivam, Pragalath
AU - Ramasamy, Boominathan
AU - Hartimath, Siddana V.
AU - Dhawan, Vikas
AU - Bednenko, Janna
AU - Colussi, Paul
AU - Wulff, Heike
AU - Pennington, Michael W.
AU - Kuyucak, Serdar
AU - Norton, Raymond S.
AU - Beeton, Christine
AU - Chandy, K. George
N1 - Funding Information:
The study was supported by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-032), NTU-SPARK grant, and the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant (to K.G.C.). R.S.N. acknowledges fellowship support from the National Health and Medical Research Council of Australia. H.M.N. and H.W. were supported by the National Institute of Neurological Disease and Stroke (NS100294). M.R.T. was supported in part by the National Institutes of Health T32 Grant HL007676. The Pathology & Histology and the Mouse Phenotyping Cores at Baylor College of Medicine are supported in part by funding from the National Institutes of Health (Grants HG006348 and CA125123). S.B. was supported by funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement No. 608765. The authors thank the patch-clamp ion channel pharmacology facility at NTU, Christopher A. MacRaild for his assistance with NMR diffusion experiments, the SOLEIL synchrotron facility for provision of synchrotron radiation facilities (Proposal 20170003), William Shepard and Martin Savko for assistance in using beamline Proxima 2A, beamline scientists from the Australian Synchrotron MX beamlines for their help with diffraction data collection, Wei Meng at the Proteomic Core Facility of the School of Biological Sciences, NTU, for assistance with mass spectrometry, and Ethan Tingfeng Lai at ForteBio for his help with the BLI assay.
PY - 2020/8/14
Y1 - 2020/8/14
N2 - 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.
AB - 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.
KW - autoimmune disease
KW - cell-penetrating peptide
KW - effector memory T cell
KW - grapevine
KW - K1.3
KW - oil palm
KW - peptide therapeutic
KW - plant defensin
KW - potassium channel
KW - rheumatoid arthritis
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UR - http://www.scopus.com/inward/citedby.url?scp=85087931715&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.0c00035
DO - 10.1021/acsptsci.0c00035
M3 - Article
AN - SCOPUS:85087931715
VL - 3
SP - 720
EP - 736
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
SN - 2575-9108
IS - 4
ER -