The statistics are grim. Schistosomiasis — a tropical disease caused by flatworms of the genus Schistosoma — kills 280,000 people annually. Moreover, 200 million people are infected with the worm, and a further 800 million or so are at risk. An effective, low-cost drug called praziquantel is available. But it is heavily and regularly prescribed and, as there is currently no vaccine or alternative drug available, the danger of schistosome parasites evolving resistance to the drug is looming. So the discovery by Ahmed Sayed and colleagues, at Illinois State University in Normal and the US National Institutes of Health (NIH) in Bethesda, Maryland, of a drug that may be as effective as praziquantel, if not more so, is good news (A. A. Sayed et al. Nature Med. doi:10.1038/nm1737; 2008).
Within their human host, schistosome parasites reside in aerobic environments — skin, blood, lungs and liver. This means they must be able to avoid damage caused by reactive oxygen species. The authors therefore took advantage of a valuable resource — the NIH Chemical Genomics Center chemical repository — to screen thousands of compounds for their ability to target the antioxidant pathway in one of the most widespread of schistosome species, Schistosoma mansoni (pictured).
The screen led to the identification of two groups of compounds, phosphinic amides and oxadiazole 2-oxides, which inhibit an enzyme known as TGR — a multifunctional agent that is uniquely responsible for the detoxification of reactive oxygen species in schistosome parasites. One oxadiazole called furoxan was particularly noteworthy for being highly potent at low doses.
Furoxan did well in subsequent tests. The authors found that, within 24 hours, drug concentrations of just 10 micromolar killed 100% of adult S. mansoni grown in culture, and concentrations of 2 micromolar had the same effect over 5 days. Moreover, furoxan was active against two other worm species that also cause schistosomiasis.
Human white blood cells produce nitric oxide, which can kill larval schistosomes. Sayed and colleagues show that, as well as inhibiting TGR activity, furoxan reacts with TGR to produce nitric oxide, increasing the compound's toxic effect on the parasite.
The authors also tested the toxicity of furoxan in mouse cell lines and found that its toxicity is not very different from that of praziquantel. Investigating the efficacy of furoxan in overcoming schistosome infection in mice revealed that, depending on the stage in the life-cycle of S. mansoni at which the drug was administered, the disease burden was reduced by at least 88%. Such efficacy exceeds the criteria set by the World Health Organization for potential lead compounds for the treatment of schistosomiasis. Furoxan is thus a highly promising compound for use as an alternative or supplement to praziquantel — the two drugs function through different mechanisms. Efforts are already under way to generate furoxan derivatives suitable for use in humans.
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Shadan, S. Schistosome treatment. Nature 452, 296 (2008). https://doi.org/10.1038/452296b
Parasitological evaluation of Ro 15-9268, a 9-acridanone-hydrazone derivative against Schistosoma mansoni in mice, and observations on changes in serum enzyme levels
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