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

Sandeep Chhabra, Shihchieh Jeff Chang, Hai M Nguyen, Redwan Huq, Mark R Tanner, Luz Marina Londono, Rosendo Estrada, Vikas Dhawan, Satendra Chauhan, Sanjeev Kumar Upadhyay, Mariel Gindin, Peter Jay Hotez, Jesus Gilberto Valenzuela, Biswaranjan Mohanty, James David Swarbrick, Heike Wulff, Shawn P Iadonato, George A Gutman, Christine Beeton, Michael William PenningtonRaymond Stanley Norton, George Kanianthara Chandy

Research output: Contribution to journalArticleResearchpeer-review

48 Citations (Scopus)

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 IFN? 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.
Original languageEnglish
Pages (from-to)3952 - 3964
Number of pages13
JournalThe FASEB Journal
Volume28
DOIs
Publication statusPublished - 2014

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