Screening the Pathogen Box for Identification of New Chemical Agents with Anti- Fasciola hepatica Activity

Abstract

Fascioliasis is an infectious parasitic disease distributed globally and caused by the liver fluke Fasciola hepatica or F. gigantica. This neglected tropical disease affects both animals and humans, and it represents a latent public health problem due to the significant economic losses related to its effects on animal husbandry. For decades, triclabendazole has been the unique anti-Fasciola drug that can effectively treat this disease. However, triclabendazole resistance in fascioliasis has more recently been reported around the world, and thus, the discovery of novel drugs is an urgent need. The aim of this study was to investigate the fasciocidal properties of 400 compounds contained in the Pathogen Box. The first stage of the screening was carried out by measuring the fasciocidal activity on metacercariae at a concentration of 33 μM each compound (the standard dose). Subsequently, the activities of the most active compounds (n = 33) at their 50% inhibitory concentration (IC50) values against metacercariae were assayed, and the results showed that 13 compounds had IC50s of ≤10 μM. The second stage queried the activities of these compounds at 33 μM against adult flukes, with seven of the compounds producing high mortality rates of >50%. Four hit compounds were selected on the basis of their predicted nontoxic properties, and the IC50 values obtained for adult worms were <10 μM; thus, these compounds represented the best fasciocidal compounds tested here. A cytotoxicity assay on four types of cell lines demonstrated that three compounds were nontoxic at their most active concentration. In conclusion, three hit compounds identified in this proof-of-concept study are potential candidates in the discovery of new fasciocidal drugs. Further studies are warranted.

Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma

“…These compound libraries contained druglike molecules previously shown to be active against pathogens causing tropical and neglected diseases (Pathogen Box) or candidates that had been studied in clinical studies and could, thus be potentially repurposed for neglected diseases (Stasis Box). These were made available by MMV as an open access initiative tool to stimulate research and development in neglected diseases [11,12]. In return, researchers were asked to share their findings in the public domain, creating an open and collaborative forum for infectious disease drug research.…”

The Schistosoma mansoni tegumental allergen protein, SmTAL1: Binding to an IQ-motif from a voltage-gated ion channel and effects of praziquantel

“…Two further screens of the MMV compounds have been carried out by the Keiser group. It should be noted that none of the compounds demonstrated to bind SmTAL1 affected either juvenile or adult schistosomes in these screens, nor are they reported to have any effect on F. hepatica [70][71][72].…”

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

“…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.…”

“…E. multilocularis metacestode screen -damage was assessed by quantifying the activity of phosphoglucose isomerase released into the culture media [162]. 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].…”