Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases
Open accessAbstract
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.—Chhabra, S., Chang, S. C., Nguyen, H. M., Huq, R., Tanner, M. R., Londono, L. M., Estrada, R., Dhawan, V., Chauhan, S., Upadhyay, S. K., Gindin, M., Hotez, P. J., Valenzuela, J. G., Mohanty, B., Swarbrick, J. D., Wulff, H., Iadonato, S. P., Gutman, G. A., Beeton, C., Pennington, M. W., Norton, R. S., Chandy, K. G. Kv1.3 channel‐blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. FASEB J. 28, 3952‐3964 (2014). www.fasebj.org
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AcK1 and BmK1 suppress a delayed-type hypersensitivity (DTH) reaction in rats.
“These peptides suppress a delayed-type hypersensitivity (DTH) reaction in rats and inhibit primarily the proliferation of memory T cells without affecting naive or central memory subsets (Chhabra et al., 2014).”
From Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules (2018) · cites this paper as Chhabra et al., 2014
AcK1 and BmK1 inhibit primarily the proliferation of memory T cells without affecting naive or central memory subsets.
“These peptides suppress a delayed-type hypersensitivity (DTH) reaction in rats and inhibit primarily the proliferation of memory T cells without affecting naive or central memory subsets (Chhabra et al., 2014).”
From Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules (2018) · cites this paper as Chhabra et al., 2014
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“ShK-186, BmK2, and truncated AcK1 (AcK1t) solutions were reconstituted in P6N (19) and diluted in complete DMEM (25 mM HEPES, 2 mM L-glutamine, 55 μM β-mercaptoethanol, and 100 IU penicillin and streptomycin) at 4 times the desired final concentration.”
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Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules
Maizels, R. M., Smits, H. H., & McSorley, H. J. (2018) · Immunity · doi:10.1016/j.immuni.2018.10.016 · Cited by 435 · see citing works
Chiang, E. Y., Li, T., Jeet, S., Peng, I., Zhang, J., Lee, W. P., DeVoss, J., Caplazi, P., Chen, J., Warming, S., et al. (2017) · Nature Communications · doi:10.1038/ncomms14644 · Cited by 108 · see citing works
- Authors
- Chhabra, S., Chang, S. C., Nguyen, H. M., Huq, R., Tanner, M. R., Londono, L. M., Estrada, R., Dhawan, V., Chauhan, S., Upadhyay, S. K., Gindin, M., Hotez, P. J., Valenzuela, J. G., Mohanty, B., Swarbrick, J. D., Wulff, H., Iadonato, S. P., Gutman, G. A., Beeton, C., Pennington, M. W., Norton, R. S., & Chandy, K. G.
- Affiliations
- Monash University (AU)
- University of California, Irvine (US)
- Baylor College of Medicine (US)
- Kineta (United States) (US)
- Peptides International (United States) (US)
- National Institutes of Health (US)
- University of California, Davis (US)
- Corresponding author
- Norton, Raymond S.
- Chandy, K. George
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2014-06-02
- Volume
- 28
- Issue
- 9
- Pages
- 3952-3964
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC4139903
- OpenAlex
- W2100819009
- Cited by
- 91
- References
- 3
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 3 · 2023: 13 · 2022: 6 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 6 · 2014: 2
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01 NS48252, NS073712, GM076063, GM088129)
- Center for Virus Research, University of California, Irvine
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Kv1.3 potassium channel, immunomodulatory peptides, helminths, hookworm, Ancylostoma caninum, Ancylostoma ceylanicum, Brugia malayi, metalloproteinases, T cell proliferation, effector memory T cells, delayed-type hypersensitivity, IFN-gamma production, probiotic therapy, autoimmune disease
- MeSH terms
- Amino Acid Sequence, Animals, Autoimmune Diseases, Cells, Cultured, Cnidarian Venoms, Electrophysiology, Female, Fibroblasts, Helminths, Humans, Hypersensitivity, Delayed, Immunologic Memory, Male, Models, Molecular, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Peptide Fragments, Phylogeny, Protein Conformation, Rats, Inbred Lew, Structure-Activity Relationship, T-Lymphocytes, Cytokines, Sequence Homology, Amino Acid, Potassium Channel Blockers, Cell Proliferation, Mice, Rats, Kv1.3 Potassium Channel, Receptors, CCR7
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