Malagón, David, Botterill, Bonnie, Gray, Darren J., Lovas, Erica, Duke, Mary, Gray, Christian, Kopp, Steven R., Knott, Lyn M., McManus, Donald P., Daly, Norelle L., Mulvenna, Jason, Craik, David J., and Jones, Malcolm K. (2013) Anthelminthic activity of the cyclotides (kalata B1 and B2) against schistosome parasites. Peptide Science, 100 (5). pp. 461-470.

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Abstract

The risk of reduced sensitivity of the human schistosomes to praziquantel has led to efforts to find new therapies. Here the cyclotides kalata B1 (kB1), kalata B2 (kB2), MCoCC-1 and MCoTI-II, cyclic peptides extracted from plants and shown to be potent against nematodes and insects, were tested for anti-schistosome activity. In vitro assays showed that high concentrations (500 - 1,000 μg/ml) of either kB1 or kB2 killed Schistosoma japonicum and S. mansoni adults within 5 minutes whereas MCoTI-II and MCoCC-1 had no effect. Lethal concentrations to kill 50% of the population for kB2 was 15.5 ±7.4 μg/ml at 1 hour for male S. japonicum (Philippine strain). Males were more susceptible than females. kB2 showed higher anti-schistosome activity than kB1. Mode of action studies revealed that kB1 and 2 lysed the tegument of adult worms. Lysis of myofibrils was not demonstrated, but longitudinal and radial muscle fibres were distorted, an observation consistent with strong coiling of the parasites after drug exposure. A single dose of kB2 administered either orally or intravenously, reduced worm burdens in S. japonicum-infected mice from 15 to 60%. However, treatment of S. mansoni-infected mice did not result in reduction in worm burdens. Our studies show that kB2 acts as a promising anti-schistosomal against Philippine S. japonicum, and it or other cyclotides may be developed further as general anthelminthics. With thousands of cyclotides occurring naturally in plants, and the susceptibility of these peptides to combinatatorial variation, there is potential for their exploitation as wide-spectrum anthelminthics.

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