Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 3952 - 3964 |
| Number of pages | 13 |
| Journal | FASEB Journal |
| Volume | 28 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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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 journal › Article › Research › peer-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 -