Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin

Seow Theng Ong; Saumya Bajaj; Mark R Tanner; Shih Chieh Chang; Bankala Krishnarjuna; Xuan Rui Ng; Rodrigo A V Morales; Ming Wei Chen; Dahai Luo; Dharmeshkumar Patel; Sabina Yasmin; Jeremy Jun Heng Ng; Zhong Zhuang; Hai M Nguyen; Abbas El Sahili; Julien Lescar; Rahul Patil; Susan A Charman; Edward G Robins; Julian L Goggi; Peng Wen Tan; Pragalath Sadasivam; Boominathan Ramasamy; Siddana V Hartimath; Vikas Dhawan; Janna Bednenko; Paul Colussi; Heike Wulff; Michael W Pennington; Serdar Kuyucak; Raymond S Norton; Christine Beeton; K George Chandy

doi:10.1021/acsptsci.0c00035

Modulation of Lymphocyte Potassium Channel K_V1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin

ACS Pharmacol Transl Sci. 2020 May 14;3(4):720-736. doi: 10.1021/acsptsci.0c00035. eCollection 2020 Aug 14.

Authors

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 Robins^{8

9}, Julian L Goggi⁸, Peng Wen Tan⁸, Pragalath Sadasivam⁸, Boominathan Ramasamy⁸, Siddana V Hartimath⁸, Vikas Dhawan^{10

11}, Janna Bednenko¹², Paul Colussi¹², Heike Wulff⁵, Michael W Pennington^{10

11}, Serdar Kuyucak⁴, Raymond S Norton^{3

13}, Christine Beeton², K George Chandy¹

Affiliations

¹ Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Experimental Medicine Building, 59 Nanyang Drive, Singapore 636921.
² Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, United States.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
⁴ School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia.
⁵ Department of Pharmacology, University of California, Davis, California 95616, United States.
⁶ School of Biological Sciences, Nanyang Institute of Structural Biology, Experimental Medicine building, Singapore 636921.
⁷ Centre for Drug Candidate Optimisation, Monash University, Parkville, Victoria 3052, Australia.
⁸ Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A Star), Singapore 138667.
⁹ Singapore Bioimaging Consortium, NUS Clinical Imaging Research Centre (CIRC), Centre for Life Sciences, Singapore 117599.
¹⁰ Peptides International, Inc., Louisville, Kentucky 40269, United States.
¹¹ AmbioPharm Inc., North Augusta, South Carolina 29842, United States.
¹² TetraGenetics Inc, Arlington, Massachusetts 02474, United States.
¹³ ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria 3052, Australia.

Abstract

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K_V1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K_V1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K_V1.3 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.

Abstract

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