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

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

Research output: Contribution to journalArticle

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 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 channelblocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)3952-3964
Number of pages13
JournalFASEB Journal
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2014

Fingerprint

Helminths
Autoimmune Diseases
T-cells
Peptides
Ancylostoma
T-Lymphocytes
Ancylostomatoidea
Data storage equipment
Rats
Brugia malayi
Voltage-Gated Potassium Channels
Immunomodulation
Helianthus
Probiotics
Delayed Hypersensitivity
Metalloproteases
Fibroblasts
Rodentia
Skin
Healthy Volunteers

Keywords

  • Hookworm
  • Ion channel modulator
  • Probiotic worm therapy
  • ShK
  • T lymphocytes

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Chhabra, S., Chang, S. C., Nguyen, H. M., Huq, R., Tanner, M. R., Londono, L. M., ... Chandy, K. G. (2014). Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases. FASEB Journal, 28(9), 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, 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.

In: FASEB Journal, Vol. 28, No. 9, 01.09.2014, p. 3952-3964.

Research output: Contribution to journalArticle

Chhabra, S, Chang, SC, 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, KG 2014, 'Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: Implications for autoimmune diseases', FASEB Journal, vol. 28, no. 9, pp. 3952-3964. https://doi.org/10.1096/fj.14-251967
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. / Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms : Implications for autoimmune diseases. In: FASEB Journal. 2014 ; Vol. 28, No. 9. pp. 3952-3964.
@article{db34fac82cf042539897b3652202e588,
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. - 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 channelblocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.",
keywords = "Hookworm, Ion channel modulator, Probiotic worm therapy, ShK, T lymphocytes",
author = "Sandeep Chhabra and Chang, {Shih Chieh} and Nguyen, {Hai M.} and Redwan Huq and Tanner, {Mark R.} and Londono, {Luz M.} and Rosendo Estrada and Vikas Dhawan and Satendra Chauhan and Upadhyay, {Sanjeev K.} and Mariel Gindin and Hotez, {Peter J.} and Valenzuela, {Jesus G.} and Biswaranjan Mohanty and Swarbrick, {James D.} and Heike Wulff and Iadonato, {Shawn P.} and Gutman, {George A.} and Christine Beeton and Pennington, {Michael W.} and Norton, {Raymond S.} and Chandy, {K. George}",
year = "2014",
month = "9",
day = "1",
doi = "10.1096/fj.14-251967",
language = "English (US)",
volume = "28",
pages = "3952--3964",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "9",

}

TY - JOUR

T1 - Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms

T2 - Implications for autoimmune diseases

AU - Chhabra, Sandeep

AU - Chang, Shih Chieh

AU - Nguyen, Hai M.

AU - Huq, Redwan

AU - Tanner, Mark R.

AU - Londono, Luz M.

AU - Estrada, Rosendo

AU - Dhawan, Vikas

AU - Chauhan, Satendra

AU - Upadhyay, Sanjeev K.

AU - Gindin, Mariel

AU - Hotez, Peter J.

AU - Valenzuela, Jesus G.

AU - Mohanty, Biswaranjan

AU - Swarbrick, James D.

AU - Wulff, Heike

AU - Iadonato, Shawn P.

AU - Gutman, George A.

AU - Beeton, Christine

AU - Pennington, Michael W.

AU - Norton, Raymond S.

AU - Chandy, K. George

PY - 2014/9/1

Y1 - 2014/9/1

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 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 channelblocking immunomodulatory peptides from parasitic worms: implications for 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 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 channelblocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

KW - Hookworm

KW - Ion channel modulator

KW - Probiotic worm therapy

KW - ShK

KW - T lymphocytes

UR - http://www.scopus.com/inward/record.url?scp=84907185220&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907185220&partnerID=8YFLogxK

U2 - 10.1096/fj.14-251967

DO - 10.1096/fj.14-251967

M3 - Article

C2 - 24891519

AN - SCOPUS:84907185220

VL - 28

SP - 3952

EP - 3964

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 9

ER -