Abstract
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.
Highlights
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs
Sertraline, paroxetine, and chlorpromazine are toxic to multiple C. elegans developmental stages
Parasitic helminths are typically present in several developmental stages in an infected human, and efficacy against more than one parasite life stage can reduce the number of treatments required or prevent the need to use a combination drug therapy targeting different life stages
Summary
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. We found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines They may represent new classes of anthelmintic drug that could be used in combination with existing frontline drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance. The journey from initial development to approval for use in humans is long and costly, and it is estimated to exceed 2.5 billion dollars to bring a single new drug to market[5]
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