Referenced in: none

Automatically associated channels: Kv1.3

Title: Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

Authors: Sandeep Chhabra, Shih Chieh Chang, Hai M Nguyen, Redwan Huq, Mark R Tanner, Luz M Londono, Rosendo Estrada, Vikas Dhawan, Satendra Chauhan, Sanjeev K Upadhyay, Mariel Gindin, Peter J Hotez, Jesus G Valenzuela, Biswaranjan Mohanty, James D Swarbrick, Heike Wulff, Shawn P Iadonato, George A Gutman, Christine Beeton, Michael W Pennington, Raymond S Norton, K George Chandy

Journal, date & volume: FASEB J., 2014 Jun 2 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24891519

Abstract
The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7(-) effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.