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Multi-center screening of the Pathogen Box collection for schistosomiasis drug discovery

Maccesi, Martina and Aguiar, Pedro H. N. and Pasche, Valérian and Padilla, Melody and Suzuki, Brian M. and Montefusco, Sandro and Abagyan, Ruben and Keiser, Jennifer and Mourão, Marina M. and Caffrey, Conor R.. (2019) Multi-center screening of the Pathogen Box collection for schistosomiasis drug discovery. Parasites and Vectors, 12 (1). p. 493.

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Abstract

Over 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.; Both 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.; For 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 Pearson's 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.; The 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 .
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 (MPI) > Helminth Drug Development (Keiser)
UniBasel Contributors:Pasche, Valérian and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:BioMed Central
ISSN:1756-3305
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:09 Dec 2019 13:19
Deposited On:09 Dec 2019 13:19

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