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Open Access Publications from the University of California

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

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

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.

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