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Background Helminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Emodepside, a marketed broad-spectrum veterinary anthelminthic with a unique mechanism of action, undergoing development for onchocerciasis is an interesting anthelmintic drug candidate. We tested the in vitro and in vivo activity of emodepside on nematode species that serve as models for human soil-transmitted helminth infection as well as on schistosomes. Methods In vitro viability assays were performed over a time course of 72 hours for Trichuris muris , Necator americanus , Ancylostoma ceylanicum , Heligmosomoides polygyrus , Strongyloides ratti , Schistosoma mansoni and Schistosoma haematobium . The drug effect was determined by the survival rate for the larvae and by phenotypical scores for the adult worms. Additionally, mice infected with T. muris and hamsters harboring hookworm infection ( N. americanus or A. ceylanicum ) were administered orally with emodepside at doses ranging from 1.25 to 75 mg/kg. Expelled worms in the feces were counted until 3 days post-drug intake and worms residing in the intestines were collected and counted after dissection. Results After 24 hours, emodepside was very active in vitro against both larval and adult stages of the nematodes T. muris , A. ceylanicum , N. americanus , H. polygyrus and S. ratti (IC 50 < 4 µM). The good in vitro activity was confirmed in vivo . Hamsters infected with the hookworms were cured when administered orally with 2.5 mg/kg of the drug. Emodepside was also highly active in vivo against T. muris (ED 50 = 1.2 mg/kg). Emodepside was moderately active on schistosomula in vitro (IC 50 < 8 µM) 24 h post-drug incubation and its activity on adult S. mansoni and S. haematobium was low (IC 50 : 30–50 µM). Conclusions Emodepside is highly active against a broad range of nematode species both in vitro and in vivo . The development of emodepside for treating soil-transmitted helminth infections should be pursued. Electronic supplementary material The online version of this article...

BackgroundThe development of new treatments against schistosomiasis is imperative but lacks commercial interest. Drug repurposing represents a suitable strategy to identify potential treatments, which have already unblocked several essential steps along the drug development path, hence reducing costs and timelines. Promoting this approach, the Medicines for Malaria Venture (MMV) recently distributed a drug repurposing library of 400 advanced lead candidates (Stasis Box).MethodsAll 400 compounds were initially tested in vitro against the larval stage of Schistosoma mansoni at 10 μM. Hits progressed to screening on adult worms and were further characterised for IC50, cytotoxicity and selectivity. Ten lead compounds were tested in mice harbouring a chronic S. mansoni infection.ResultsEleven of the 37 compounds active on the larval stage were also highly active on adult worms in vitro (IC50 = 2.0–7.5 μM). IC50 values on adult S. mansoni decreased substantially in the presence of albumin (7.5–123.5 μM). Toxicity to L6 and MRC cells was moderate. A moderate worm burden reduction of 51.6% was observed for MMV690534, while the other 9 compounds showed low activity. None of the in vivo results were statistically significant (P > 0.05).ConclusionsPhenotypic screening of advanced lead compounds is a simple and resource-low method to identify novel anthelminthics. None of the promising hits of the Stasis Box identified in vitro against S. mansoni yielded acceptable worm burden reductions in vivo, which might be due to the high plasma protein binding. Since the in vitro hits interfere with different drug targets, they might provide a starting point for target based screening and structure-activity relationship studies.

BackgroundOver the past five years, as a public service to encourage and accelerate drug discovery for diseases of poverty, the Medicines for Malaria Venture (MMV) has released box sets of 400 compounds named the Malaria, Pathogen and Stasis Boxes. Here, we screened the Pathogen Box against the post-infective larvae (schistosomula) of Schistosoma mansoni using assays particular to the three contributing institutions, namely, the University of California San Diego (UCSD) in the USA, the Swiss Tropical and Public Health Institute (Swiss TPH) in Switzerland, and the Fundação Oswaldo Cruz (FIOCRUZ) in Brazil. With the same set of compounds, the goal was to determine the degree of inter-assay variability and identify a core set of active compounds common to all three assays. New drugs for schistosomiasis would be welcome given that current treatment and control strategies rely on chemotherapy with just one drug, praziquantel.MethodsBoth the UCSD and Swiss TPH assays utilize daily observational scoring methodologies over 72 h, whereas the FIOCRUZ assay employs XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) at 72 h to measure viability as a function of NAD+/NADH redox state. Raw and transformed data arising from each assay were assembled for comparative analysis.ResultsFor the UCSD and Swiss TPH assays, there was strong concordance of at least 87% in identifying active and inactive compounds on one or more of the three days. When all three assays were compared at 72 h, concordance remained a robust 74%. Further, robust Pearsonʼs correlations (0.48–0.68) were measured between the assays. Of those actives at 72 h, the UCSD, Swiss TPH and FIOCRUZ assays identified 86, 103 and 66 compounds, respectively, of which 35 were common. Assay idiosyncrasies included the identification of unique compounds, the differential ability to identify known antischistosomal compounds and the concept that compounds of interest might include those that increase metabolic activity above baseline.ConclusionsThe inter-assay data generated were in good agreement, including with previously reported data. A common set of antischistosomal molecules for further exploration has been identified.

As part of the control and elimination strategy of human schistosomiasis, preventive chemotherapy relies on a single drug, praziquantel. Facing an almost dry drug development pipeline, screening the Pathogen Box from the Medicines for Malaria Venture (MMV), provides a unique opportunity to possibly expand the pool of potent molecules against schistosomiasis. The activity of 400 compounds from this open-access library was first screened in vitro on the larval stage of Schistosoma mansoni. The hits were then tested on adult worms. Eleven leads were identified and tested for albumin-binding and activity on adult S. haematobium. In parallel, a rudimental structure–activity relationship analysis was performed on the 112 available analogues of three leads, yielding another 30 molecules active against both larval and adult stages of S. mansoni. Seven leads, selected on druglikeness, pharmacokinetic properties, and availability, plus auranofin were tested in mice harboring a chronic S. mansoni infection. MMV022029 and MMV022478 revealed the highest worm burden reductions of 67.8 and 70.7%, respectively. This study provided a series of new potent scaffolds and pharmacophores that could be used to design and develop suitable alternative(s) to praziquantel.