Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

Mäder, Patrick; Rennar, Georg A.; Ventura, Alejandra M. Peter; Grevelding, Christoph G.; Schlitzer, Martin

doi:10.1002/cmdc.201800572

Cited by 37 publications

(23 citation statements)

References 213 publications

(466 reference statements)

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“…The life cycle of this parasite features an uncommon relationship between the male and female parasites, whereby signal‐transduction pathways activated by the male result in proliferation and differentiation of cells located within the reproductive organs, leading to large‐scale egg production …”

Section: Schistosomiasismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Schistosomiasismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…However, there are concerns about the development of resistance to these drugs; triclabendazole resistance of P. westermani was reported in a human case from Korea [ 54 ]. Furthermore, there is widespread resistance to triclabendazole in liver flukes in cattle in Australia and South America [ 55 ], and praziquantel resistance is anticipated in the future owing to its widespread use as a single treatment for schistosomiasis, a worrisome situation that has encouraged the search for novel drugs [ 56 ]. The comparative analysis presented here identifies valuable putative protein targets for drug development, including Paragonimus -specific proteins and trematode-conserved proteins that do not share orthology to human proteins.…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics and transcriptomics of 4 Paragonimus species provide insights into lung fluke parasitism and pathogenesis

et al. 2020

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Background Paragonimus spp. (lung flukes) are among the most injurious foodborne helminths, infecting ∼23 million people and subjecting ∼292 million to infection risk. Paragonimiasis is acquired from infected undercooked crustaceans and primarily affects the lungs but often causes lesions elsewhere including the brain. The disease is easily mistaken for tuberculosis owing to similar pulmonary symptoms, and accordingly, diagnostics are in demand. Results We assembled, annotated, and compared draft genomes of 4 prevalent and distinct Paragonimus species: Paragonimus miyazakii, Paragonimus westermani, Paragonimus kellicotti, and Paragonimus heterotremus. Genomes ranged from 697 to 923 Mb, included 12,072–12,853 genes, and were 71.6–90.1% complete according to BUSCO. Orthologous group analysis spanning 21 species (lung, liver, and blood flukes, additional platyhelminths, and hosts) provided insights into lung fluke biology. We identified 256 lung fluke–specific and conserved orthologous groups with consistent transcriptional adult-stage Paragonimus expression profiles and enriched for iron acquisition, immune modulation, and other parasite functions. Previously identified Paragonimus diagnostic antigens were matched to genes, providing an opportunity to optimize and ensure pan-Paragonimus reactivity for diagnostic assays. Conclusions This report provides advances in molecular understanding of Paragonimus and underpins future studies into the biology, evolution, and pathogenesis of Paragonimus and related foodborne flukes. We anticipate that these novel genomic and transcriptomic resources will be invaluable for future lung fluke research.

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“…After penetrating the final host, cercariae develop into schistosomula (juvenile stage) and later into adult worms. [2,5] With respect to their relevance for human health, three speciesa re most common: S. mansoni, S. japonicum and S. haematobium. All three species localisei nd ifferentp arts of the body but cause similar symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…[6] Praziquantel (PZQ) is the only drug that is widely used against all schistosome species (Figure 1). [2] An advantage of this drug is its efficacy toward all schistosome species and its low cost for treatment. [7] If 60 mg kg À1 of PZQ is administered orally on three consecutive days, a 90 %c ure rate can be achieved.…”

Section: Introductionmentioning

confidence: 99%

“…[10,11] Therefore, the development of new potential anti-schistosomal agents is urgently needed. [2] The schistosomal aldose reductase (AR) is thought to play an important role in antioxidant pathways and protection of the worms from attack by its host's reactive oxygen species. [12,13] This makes schistosomal AR an interesting target for novel anti-schistosomal inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Development of Biarylalkyl Carboxylic Acid Amides with Improved Anti‐schistosomal Activity

et al. 2019

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The parasitic disease schistosomiasis is the cause of more than 200 000 human deaths per year. Although the disease is treatable, there is one major shortcoming: praziquantel has been the only drug used to combat these parasites since 1977. The risk of the emergence of resistant schistosomes is known to be increasing, as a reduced sensitivity of these parasites toward praziquantel has been observed. We developed a new class of substances, which are derived from inhibitors of human aldose reductase, and which showed promising activity against Schistosoma mansoni couples in vitro. Further optimisation of the compounds led to an increase in anti‐schistosomal activity with observed phenotypes such as reduced egg production, vitality, and motility as well as tegumental damage and gut dilatation. Here, we performed structure–activity relationship studies on the carboxylic acid moiety of biarylalkyl carboxylic acids. Out of 82 carboxylic acid amides, we identified 10 compounds that are active against S. mansoni at 25 μm. The best five compounds showed an anti‐schistosomal activity up to 10 μm and induced severe phenotypes. Cytotoxicity tests in human cell lines showed that two derivatives had no cytotoxicity at 50 or 100 μm. These compounds are promising candidates for further optimisation toward the new anti‐schistosomal agents.

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Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

Cited by 37 publications

References 213 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Comparative genomics and transcriptomics of 4 Paragonimus species provide insights into lung fluke parasitism and pathogenesis

Development of Biarylalkyl Carboxylic Acid Amides with Improved Anti‐schistosomal Activity

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