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Early antischistosomal leads identified from in vitro and in vivo screening of the medicines for malaria venture pathogen box

Pasche, Valérian and Laleu, Benoît and Keiser, Jennifer. (2018) Early antischistosomal leads identified from in vitro and in vivo screening of the medicines for malaria venture pathogen box. ACS infectious diseases, 5 (1). pp. 102-110.

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Official URL: https://edoc.unibas.ch/68746/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Pasche, Valérian and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:ACS Publications
ISSN:2373-8227
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 Jan 2019 14:47
Deposited On:29 Jan 2019 14:47

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