orals 5th Asia-Pacific NMR Symposium 2013

New Kv1.3 channel-blocking immunomodulatory peptides from worms (#54)

Sandeep Chhabra 1 , Hai M. Nguyen 2 , Shih C. Chang 1 , James D. Swarbrick 1 , Biswaranjan Mohanty 1 , Christine Beeton 3 , Michael W. Pennington 4 , George K. Chandy 2 , Raymond S. Norton 1
  1. MIPS (Monash institute of Pharmaceutical Sciences), Parkville, VIC, 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
  4. Peptides International , 11621 Electron Drive, Louisville , KY 40299, USA

Autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), ulcerative colitis and Crohn’s disease 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 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 the immune system. These cells dampen the immune response and curb autoimmunity by stimulating release of cytokines, which in turn prevent the production of effector T cells (Teff) responsible for triggering autoimmune reactions.
Autoimmune disease patients treated with parasitic worm infections showed improved disease symptoms and had no adverse effects (1). 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. Our aim is to identify 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 two types of worm peptides, one that is secreted as a peptide and other as the C-terminal domain of a larger protein. The solution structures of both peptides were solved using conventional NMR experiments. Our initial electrophysiological data suggest that both peptides are Kv1.3 potassium channel blockers. Currently, we are investigating the ability of these peptides to suppress human T cell production of cytokines and effector memory T cell proliferation. These peptides may contribute to the immunosuppressant activity of parasitic worms and may serve as potential drug candidates in the therapy of autoimmune diseases.

  1. Weinstock JV (2012) Autoimmunity: The worm returns. Nature 491(7423):183-185.