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

Pasche, Valérian; Laleu, Benoît; Keiser, Jennifer

doi:10.1021/acsinfecdis.8b00220

Cited by 23 publications

(17 citation statements)

References 34 publications

(57 reference statements)

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“…Overall, a common core set of 35 active compounds was identified which could be considered for further investigation. In this context, the activity of 24 out of the 35 core actives has already been tested against adult S. mansoni [15] with 13 compounds being active on both developmental stages (Additional file 1: Table S9). These particular hits provide starting points for further optimization.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…Each compound is active against a particular pathogen and the whole box covers 13 pathogens responsible for different neglected tropical diseases. Since its release, the Pathogen Box has been tested on multiple targets reported to inhibit pathogenic fungi [37,38], helminths including Haemonchus contortus [39], Schistosoma mansoni , and Schistosoma haematobium [40], and apicomplexa including Toxoplasma gondii [41], Cryptosporidium parvum [42], P. falciparum [43], and Neospora caninum [44]. Importantly, screening against P. falciparum identified a potent inhibitor, MMV390048, that targets Plasmodium phosphatidylinositol 4-kinase at an IC 50 of 28 nM [43].…”

Section: Discussionmentioning

confidence: 99%

Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box

Wang

Miyazaki

Inaoka

et al. 2019

Genes

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Malaria is one of the three major global health threats. Drug development for malaria, especially for its most dangerous form caused by Plasmodium falciparum, remains an urgent task due to the emerging drug-resistant parasites. Exploration of novel antimalarial drug targets identified a trifunctional enzyme, malate quinone oxidoreductase (MQO), located in the mitochondrial inner membrane of P. falciparum (PfMQO). PfMQO is involved in the pathways of mitochondrial electron transport chain, tricarboxylic acid cycle, and fumarate cycle. Recent studies have shown that MQO is essential for P. falciparum survival in asexual stage and for the development of experiment cerebral malaria in the murine parasite P. berghei, providing genetic validation of MQO as a drug target. However, chemical validation of MQO, as a target, remains unexplored. In this study, we used active recombinant protein rPfMQO overexpressed in bacterial membrane fractions to screen a total of 400 compounds from the Pathogen Box, released by Medicines for Malaria Venture. The screening identified seven hit compounds targeting rPfMQO with an IC50 of under 5 μM. We tested the activity of hit compounds against the growth of 3D7 wildtype strain of P. falciparum, among which four compounds showed an IC50 from low to sub-micromolar concentrations, suggesting that PfMQO is indeed a potential antimalarial drug target.

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“…The Pathogen Box project is currently active, but several groups have already reported anthelmintic screens using this library [129,135,[161][162][163][164][165]. We have compiled the results from these published screens in Figure 5.…”

Section: Open Approaches To Developing Therapeuticsmentioning

confidence: 99%

“…F. hepatica screens -viability of metacercariae was assessed using a scoring system taking into account membrane damage and fluke translucency, and viability of adults was assessed using a scoring system taking into account worm motility, colour and rigidity [165]. H. contortus screen -automated quantification of motility of exsheathed L3 worms [129], S. haematobium and S. mansoni screens -activity was assessed using a scoring system taking into account motility and morphological/tegumental changes [161]. [161]) and the cestode E. multilocularis [162].…”

Section: Open Approaches To Developing Therapeuticsmentioning

confidence: 99%

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Anthelmintic drug discovery: target identification, screening methods and the role of open science

Partridge¹,

Forman²,

Bataille³

et al. 2020

Beilstein J. Org. Chem.

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Helminths, including cestodes, nematodes and trematodes, are a huge global health burden, infecting hundreds of millions of people. In many cases, existing drugs such as benzimidazoles, diethylcarbamazine, ivermectin and praziquantel are insufficiently efficacious, contraindicated in some populations, or at risk of the development of resistance, thereby impeding progress towards World Health Organization goals to control or eliminate these neglected tropical diseases. However, there has been limited recent progress in developing new drugs for these diseases due to lack of commercial attractiveness, leading to the introduction of novel, more efficient models for drug innovation that attempt to reduce the cost of research and development. Open science aims to achieve this by encouraging collaboration and the sharing of data and resources between organisations. In this review we discuss how open science has been applied to anthelmintic drug discovery. Open resources, including genomic information from many parasites, are enabling the identification of targets for new antiparasitic agents. Phenotypic screening remains important, and there has been much progress in open-source systems for compound screening with parasites, including motility assays but also high content assays with more detailed investigation of helminth physiology. Distributed open science compound screening programs, such as the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has been much progress in creating more potent and selective derivatives. This work exemplifies how open science approaches can catalyse drug discovery against neglected diseases.

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

Cited by 23 publications

References 34 publications

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

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

Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box

Anthelmintic drug discovery: target identification, screening methods and the role of open science

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