Discovery of a novel Kv1.3 ion channel blocker and a natural immunosuppressant peptide in a hookworm — ASN Events
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  3. Discovery of a novel Kv1.3 ion channel blocker and a natural immunosuppressant peptide in a hookworm

Discovery of a novel Kv1.3 ion channel blocker and a natural immunosuppressant peptide in a hookworm (#226)

Sandeep Chhabra 1 , Shih C. Chang 1 , Hai M. Nguyen 2 , Christine Beeton 3 , George K. Chandy 2 , Raymond S. Norton 1
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Vic-3052, Australia
  2. Departments of Physiology and Biophysics, Pharmacology, and Microbiology and Molecular Genetics, School of Medicine, University of California, , Irvine, CA 92697, USA
  3. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA

Autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), are characterized by an immune-mediated attack on the body’s own tissues. The autoimmune disorders are found to be more frequent in the affluent population of developed countries (1) owing to improved hygiene, vaccination, and the use of antibiotics. The ‘hygiene hypothesis’ states that the limited exposure to bacterial and viral infections during early childhood results in an insufficient stimulation of regulatory T cells (Treg), which results in poor development of immune system. 

Autoimmune disease patients treated with parasitic worm infections showed improved disease symptoms and had no adverse effects. However, infants and elderly patients have an underdeveloped or compromised immune system and treatment with parasite infections may increase their susceptibility to other bacterial and viral infections. Therefore, our aim is to develop new drugs based on substances secreted by the parasites into the host system and test for their ability to modulate the immune system.

In the current study, we have identified and characterized a novel hookworm (Ancylostoma caninum) secretory peptide (AcShK) (2), which is similar to the sea anemone ShK toxin although larger (AcShK is a 51-residue peptide). A recombinant expression system was designed to generate isotopically-labelled peptide in high yield. The designed construct expresses the AcShK peptide as a thioredoxin fusion protein with a TEV cleavage site. Ni2+ iminodiacetic acid affinity chromatography and reverse-phase HPLC were used to purify the peptide to homogeneity. The NMR solution structure of the peptide was solved using a doubly labelled (U-15N, 13C) sample. Initial electrophysiological experiments suggest that AcShK is a selective Kv1.3 ion channel blocker. Currently, we are investigating the ability of AcShK to suppress the human T cell production of cytokines and effector memory T cell proliferation. In conclusion this peptide may be useful as an immunosuppressant and will serve as a potential drug candidate in the therapy of autoimmune diseases.

  1. 1. Weinstock JV (2012) Autoimmunity: The worm returns. Nature 491(7423):183-185. 2. Mulvenna J, et al. (2009) Proteomics analysis of the excretory/secretory component of the blood-feeding stage of the hookworm, Ancylostoma caninum. Molecular & cellular proteomics : MCP 8(1):109-121.