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 Pennington & 2 others Raymond Stanley Norton, George Kanianthara Chandy

Research output: Contribution to journalArticleResearchpeer-review

37 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
JournalFASEB Journal
Volume28
DOIs
Publication statusPublished - 2014

Cite this

Chhabra, S., Chang, S. J., Nguyen, H. M., Huq, R., Tanner, M. R., Londono, L. M., ... Chandy, G. K. (2014). Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases. FASEB Journal, 28, 3952 - 3964. https://doi.org/10.1096/fj.14-251967
Chhabra, Sandeep ; Chang, Shihchieh Jeff ; Nguyen, Hai M ; Huq, Redwan ; Tanner, Mark R ; Londono, Luz Marina ; Estrada, Rosendo ; Dhawan, Vikas ; Chauhan, Satendra ; Upadhyay, Sanjeev Kumar ; Gindin, Mariel ; Hotez, Peter Jay ; Valenzuela, Jesus Gilberto ; Mohanty, Biswaranjan ; Swarbrick, James David ; Wulff, Heike ; Iadonato, Shawn P ; Gutman, George A ; Beeton, Christine ; Pennington, Michael William ; Norton, Raymond Stanley ; Chandy, George Kanianthara. / Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases. In: FASEB Journal. 2014 ; Vol. 28. pp. 3952 - 3964.
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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 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.",
author = "Sandeep Chhabra and Chang, {Shihchieh Jeff} and Nguyen, {Hai M} and Redwan Huq and Tanner, {Mark R} and Londono, {Luz Marina} and Rosendo Estrada and Vikas Dhawan and Satendra Chauhan and Upadhyay, {Sanjeev Kumar} and Mariel Gindin and Hotez, {Peter Jay} and Valenzuela, {Jesus Gilberto} and Biswaranjan Mohanty and Swarbrick, {James David} and Heike Wulff and Iadonato, {Shawn P} and Gutman, {George A} and Christine Beeton and Pennington, {Michael William} and Norton, {Raymond Stanley} and Chandy, {George Kanianthara}",
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doi = "10.1096/fj.14-251967",
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Chhabra, S, Chang, SJ, Nguyen, HM, Huq, R, Tanner, MR, Londono, LM, Estrada, R, Dhawan, V, Chauhan, S, Upadhyay, SK, Gindin, M, Hotez, PJ, Valenzuela, JG, Mohanty, B, Swarbrick, JD, Wulff, H, Iadonato, SP, Gutman, GA, Beeton, C, Pennington, MW, Norton, RS & Chandy, GK 2014, 'Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases', FASEB Journal, vol. 28, pp. 3952 - 3964. https://doi.org/10.1096/fj.14-251967

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases. / Chhabra, Sandeep; Chang, Shihchieh Jeff; Nguyen, Hai M; Huq, Redwan; Tanner, Mark R; Londono, Luz Marina; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Upadhyay, Sanjeev Kumar; Gindin, Mariel; Hotez, Peter Jay; Valenzuela, Jesus Gilberto; Mohanty, Biswaranjan; Swarbrick, James David; Wulff, Heike; Iadonato, Shawn P; Gutman, George A; Beeton, Christine; Pennington, Michael William; Norton, Raymond Stanley; Chandy, George Kanianthara.

In: FASEB Journal, Vol. 28, 2014, p. 3952 - 3964.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases

AU - Chhabra, Sandeep

AU - Chang, Shihchieh Jeff

AU - Nguyen, Hai M

AU - Huq, Redwan

AU - Tanner, Mark R

AU - Londono, Luz Marina

AU - Estrada, Rosendo

AU - Dhawan, Vikas

AU - Chauhan, Satendra

AU - Upadhyay, Sanjeev Kumar

AU - Gindin, Mariel

AU - Hotez, Peter Jay

AU - Valenzuela, Jesus Gilberto

AU - Mohanty, Biswaranjan

AU - Swarbrick, James David

AU - Wulff, Heike

AU - Iadonato, Shawn P

AU - Gutman, George A

AU - Beeton, Christine

AU - Pennington, Michael William

AU - Norton, Raymond Stanley

AU - Chandy, George Kanianthara

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.fasebj.org/content/28/9/3952.full.pdf+html

U2 - 10.1096/fj.14-251967

DO - 10.1096/fj.14-251967

M3 - Article

VL - 28

SP - 3952

EP - 3964

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

ER -