Early Antischistosomal Leads Identified from in Vitro and in Vivo Screening of the Medicines for Malaria Venture Pathogen Box

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Abstract
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.
Funding Information
  • FP7 Ideas: European Research Council (614739-A_HERO)

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