Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis

Rufener, Reto; Dick, Luca; D'Ascoli, Laura; Ritler, Dominic; Hizem, Amani; Wells, Timothy N. C.; Hemphill, Andrew; Lundström‐Stadelmann, Britta

doi:10.1016/j.ijpddr.2018.10.011

Cited by 45 publications

(62 citation statements)

References 65 publications

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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%

“…C. elegans viability screen -automated quantification of viability by differential absorption of the dyes DB-1 and propidium iodide [164]. 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].…”

Section: Open Approaches To Developing Therapeuticsmentioning

confidence: 99%

“…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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Section: Open Approaches To Developing Therapeuticsmentioning

confidence: 99%

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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“…• Anti-theilerial drugs MMV689480 (buparvaquone) and MMV671636 (ELQ-400) have demonstrated a cytotoxic effect [29]. Buparvaquone impaired parasite mitochondria, and with an IC50 of 2.87 μM and 0.02 μM, respectively, against in vitro cultured E. multilocularis metacestodes, buparvaquone can be an effective therapeutic choice [31].…”

Section: The Current State Of Knowledgementioning

confidence: 99%

Medical Treatment of Cystic Echinococcosis

Dumitru¹

2020

Overview on Echinococcosis

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Medical treatment in cystic echinococcosis is limited; albendazole remains the gold treatment for patients with low hydatid cysts or those with inoperable echinococcosis. Due to uncommon side effects, administration may be continuous (cycles of 28 days with a break of 14 days between courses) as well as discontinuous over long periods of time. In recent years, there have been many concerns for the testing of various substances and drugs against Echinococcus granulosus, both in vitro and in vivo, on the animal model, but the results have not been satisfactory. New clinical trials are required, as well as the development of an effective vaccine to limit the spread of echinococcosis in endemic areas.

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“…Dual activity against Giardia and Cryptosporidium were reported for MMV010576, MMV028694 and MMV676501 that showed ≥ 75% inhibitory efficacy 8 . Several such studies have accelerated the identification of small molecules that are now re-profiled, repurposed and reclassified to show broader inhibitory activities on more than one pathogenic agent 9–12 .…”

Section: Introductionmentioning

confidence: 99%

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Patra

Hingamire

Belekar

et al. 2019

Preprint

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30We report a systematic, cellular phenotype-based antimalarial screening of the MMV Pathogen Box 31 collection, which facilitated the identification of specific blockers of late stage intraerythrocytic 32 Plasmodium falciparum maturation. First, from standard growth inhibition asays, we discovered 62 33 additional antimalarials (EC 50 ≤ 10µM) over previously known antimalarial candidates from Pathogen 34 Box. A total of 90 potent molecules (EC 50 ≤ 1µM) were selected for evaluating their stage-specific 35 effects during the intra-erythrocytic development of P. falciparum. None of these molecules had 36 significant effect on ring-trophozoite transition, 10 molecules inhibited trophozoite-schizont transition, 37 and 21 molecules inhibited schizont-ring transition at 1µM. These compounds were further validated 38 in secondary assays by flow cytometry and microscopic imaging of treated cells to prioritize 12 39 molecules as potent and selective blockers of schizont-ring transition. Seven of these were found to 40 strongly inhibit calcium ionophore induced egress of Toxoplasma gondii, a related apicomplexan 41 parasite, suggesting that the inhibitors may be acting via similar mechanism in the two parasites, 42 which can be further exploited for target identification studies. Two of these molecules, with previously 43 unknown mechanism of action, MMV020670 and MMV026356, were found to induce fragmentation of 44 DNA in developing merozoites. Further mechanistic studies would facilitate therapeutic exploitation of 45 these molecules as broadly active inhibitors targeting development and egress of apicomplexan 46 parasites relevant to human health. 47 48 49 Despite technological advancements and improved knowledge on disease manifestation and 69 pathogen biology, progress in therapeutic development has been slower than expected for human 70 infectious diseases affecting the developing world. In addition to limited financial prospects, 71 pharmaceutical companies remain under significant pressure to address high attrition rates. In this 72 context, repurposing of old drugs is becoming a viable alternative through the exploitation of known 73 compounds with established mechanisms thereby shortening the time window between efficacy 74 testing to pharmacophore optimization 1-3 to eventual application. In recent efforts to speed up the 75 process of drug development against various pathogenic diseases, a collaborative model of public-76 private partnerships (PPPs) facilitated through Medicines for Malaria Venture (MMV: mmv.org) was 77 formed. This resulted in well-characterized drug-like small molecule libraries being made accessible 78 to academics worldwide, for the purpose of identifying novel bioactivities against various tropical 79 disease pathogens and conducting focused mechanistic studies. In 2015, the consortium launched 80 the open access "Pathogen Box" consisting of 400 drug-like small molecules, included 26 reference 81 compounds, with confirmed bioactivity against at least one of the neglected disease pathogens ...

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Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis

Cited by 45 publications

References 65 publications

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

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

Medical Treatment of Cystic Echinococcosis

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

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