Abstract
The human whipworm Trichuris trichiura is a parasite that infects around 500 million people globally, with consequences including damage to physical growth and educational performance. Current drugs such as mebendazole have a notable lack of efficacy against whipworm, compared to other soil-transmitted helminths. Mass drug administration programs are therefore unlikely to achieve eradication and new treatments for trichuriasis are desperately needed. All current drug control strategies focus on post-infection eradication, targeting the parasite in vivo. Here we propose developing novel anthelmintics which target the egg stage of the parasite in the soil as an adjunct environmental strategy. As evidence in support of such an approach we describe the actions of a new class of anthelmintic compounds, the 2,4-diaminothieno[3,2-d]pyrimidines (DATPs). This compound class has found broad utility in medicinal chemistry, but has not previously been described as having anthelmintic activity. Importantly, these compounds show efficacy against not only the adult parasite, but also both the embryonated and unembryonated egg stages and thereby may enable a break in the parasite lifecycle.
Highlights
Current anthelminticsThe benzimidazole anthelmintics albendazole and mebendazole are typically used to treat human whipworm infection but are compromised by lack of single-dose efficacy and the risk of resistance
This screen was designed to identify compounds active on Trichuris as existing drugs are notably less efficacious against this nematode, and it is comparatively evolutionarily distant to nematodes typically screened in anthelmintic-discovery efforts, such as H. contortus, M. incognita and C. elegans
In this report we describe the identification of a second new anthelmintic chemotype from this screen
Summary
Current anthelminticsThe benzimidazole anthelmintics albendazole and mebendazole are typically used to treat human whipworm infection but are compromised by lack of single-dose efficacy and the risk of resistance. Existing drugs lack sufficient efficacy in mass drug administration (MDA) programs to adequately control or potentially eradicate whipworm This is a major stumbling block in the WHO target to eliminate morbidity from soil transmitted helminthiases in children by 2020. For infection with T. trichiura, single doses of benzimidazoles lead to low cure rates, only 28% and 36% for albendazole and mebendazole respectively [2]. These cure rates are much lower than those of other major human soil-transmitted helminths, Ascaris lumbricoides and hookworm, demonstrating the need for improvements to therapy targeting Trichuris. Modelling studies have demonstrated that, due to these low cure rates, MDA with benzimidazoles does not interrupt whipworm transmission and cannot achieve eradication in many settings [3]
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