title: Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.
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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Sandeep
authors.initials: S
authors.lastname: Chhabra
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Shih Chieh
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA; Department of Pharmacology, University of California, Davis, California, USA;
authors.forename: Hai M
authors.initials: HM
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Physiology and Biophysics, Graduate Program in Molecular Physiology and Biophysics, and.
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.affiliation: Department of Molecular Physiology and Biophysics, Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, and.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.affiliation: Kineta, Inc., Seattle, Washington, USA;
authors.forename: Luz M
authors.initials: LM
authors.lastname: Londono
authors.affiliation: Peptides International, Louisville, Kentucky, USA;
authors.forename: Rosendo
authors.initials: R
authors.lastname: Estrada
authors.affiliation: Peptides International, Louisville, Kentucky, USA;
authors.forename: Vikas
authors.initials: V
authors.lastname: Dhawan
authors.affiliation: Peptides International, Louisville, Kentucky, USA;
authors.forename: Satendra
authors.initials: S
authors.lastname: Chauhan
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA;
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Upadhyay
authors.affiliation: Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington D.C., USA; and Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mariel
authors.initials: M
authors.lastname: Gindin
authors.affiliation: Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, USA;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hotez
authors.affiliation: Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Valenzuela
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Mohanty
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: James D
authors.initials: JD
authors.lastname: Swarbrick
authors.affiliation: Department of Pharmacology, University of California, Davis, California, USA;
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Kineta, Inc., Seattle, Washington, USA;
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Iadonato
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA;
authors.forename: George A
authors.initials: GA
authors.lastname: Gutman
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
authors.affiliation: Peptides International, Louisville, Kentucky, USA;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; gchandy@uci.edu ray.norton@monash.edu.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA; gchandy@uci.edu ray.norton@monash.edu.
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003064:Cnidarian Venoms / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006376:Helminths / Q000378:metabolism*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007156:Immunologic Memory / Q000187:drug effects*; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010802:Phylogeny; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D011917:Rats, Inbred Lew; D054400:Receptors, CCR7 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: C515370:CCR7 protein, human; D003064:Cnidarian Venoms; D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D054400:Receptors, CCR7; C095391:ShK neurotoxin
keywords: ShK; T lymphocytes; hookworm; ion channel modulator; probiotic worm therapy