A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus

Preston, Sarah; Jabbar, Abdul; Gasser, Robin B.

doi:10.1016/j.meegid.2015.06.029

Cited by 20 publications

(10 citation statements)

References 71 publications

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“…After 72 h, the plates were agitated (126 rotations per min) using an orbital shaker (model EOM5, Ratek, Australia) for 20 min at 38 °C. In order to capture the motility of xL3s at 72 h, a video recording (5 sec) was taken of each well on each plate as described previously (Preston et al., 2016a). Each 5 sec-video capture of each well was processed using a custom macro in the program Image J (1.47v, imagej.nih.gov/ij), which indirectly measured larval motility by quantifying the changes in light intensity over time (cf.…”

Section: Methodsmentioning

confidence: 99%

“…Each 5 sec-video capture of each well was processed using a custom macro in the program Image J (1.47v, imagej.nih.gov/ij), which indirectly measured larval motility by quantifying the changes in light intensity over time (cf. Preston et al., 2016a). …”

Section: Methodsmentioning

confidence: 99%

“…The motility of L4s was evaluated using the same protocol as for xL3 (see Subsection 2.2.3; Preston et al., 2016a). Following the measurement of larval motility, plates were re-incubated for four more days in a humidified environment (water-jacketed CO 2 incubator) at 38 °C and 10% v/v CO 2 .…”

Section: Methodsmentioning

confidence: 99%

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Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Preston

Jiao

Baell

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the ‘Open Scaffolds’ collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the ‘Open Scaffolds’ collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, “coiled” xL3 phenotype (IC50 = 3.46–5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31–12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3–50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50–100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Preston

Jiao

Baell

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…In addition, we applied the following default selection criteria (cf. [ 37 ]): we only considered binding assays (“B”) that reported “activity” (in %), “inhibition” (in %), “Kd” (dissociation constant in nM), “Ki” (inhibitor constant in nM), “IC50” (half-maximal inhibitory concentration in nM) or “potency” (in nM). For all values reported in nM, we set the cut-off at ≤ 10,000 nM (10 mM) and, for all percentage values, we set the cut-off at ≥ 70%, in order to pre-filter the ChEMBL database for compounds that showed activity against an associated target and are thus predicted to have an effect on an orthologous protein in the parasite.…”

Section: Introductionmentioning

confidence: 99%

Interactive online application for the prediction, ranking and prioritisation of drug targets in Schistosoma haematobium

et al. 2018

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BackgroundHuman schistosomiasis is a neglected tropical disease caused by parasitic worms of the genus Schistosoma that still affects some 200 million people. The mainstay of schistosomiasis control is a single drug, praziquantel. The reliance on this drug carries a risk of resistance emerging to this anthelmintic, such that research towards alternative anti-schistosomal drugs is warranted. In this context, a number of studies have employed computational approaches to prioritise proteins for investigation as drug targets, based on extensive genomic, transcriptomic and small-molecule data now available.MethodsHere, we established a customisable, online application for the prioritisation of drug targets and applied it, for the first time, to the entire inferred proteome of S. haematobium. This application enables selection of weighted and ranked proteins representing potential drug targets, and integrates transcriptional data, orthology and gene essentiality information as well as drug-drug target associations and chemical properties of predicted ligands.ResultsUsing this application, we defined 25 potential drug targets in S. haematobium that associated with approved drugs, and 3402 targets that (although they could not be linked to any compounds) are conserved among a range of socioeconomically important flatworm species and might represent targets for new trematocides.ConclusionsThe online application developed here represents an interactive, customisable, expandable and reproducible drug target ranking and prioritisation approach that should be useful for the prediction of drug targets in schistosomes and other species of parasitic worms in the future. We have demonstrated the utility of this online application by predicting potential drug targets in S. haematobium that can now be evaluated using functional genomics tools and/or small molecules, to establish whether they are indeed essential for parasite survival, and to assist in the discovery of novel anti-schistosomal compounds.Electronic supplementary materialThe online version of this article (10.1186/s13071-018-3197-6) contains supplementary material, which is available to authorized users.

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“…In public-private and cross-disciplinary partnerships, we have developed an efficient whole-organism drug-screening assay for H. contortus for the discovery and subsequent repurposing of compounds to parasitic nematodes [ 14 – 16 ]. Interestingly, recent reports have shown that some selective estrogen receptor modulators (SERMs) have considerable activity against protistan parasites, such as Leishmania [ 17 – 19 ] and cestodes, including Echinococcus granulosus, Taenia crassiceps and T. solium [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

et al. 2016

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BackgroundParasitic worms represent a substantial disease burden in animals and humans worldwide. The control of parasitic roundworms (nematodes) relies heavily on the use of anthelmintic drugs. However, widespread drug resistance in nematodes seriously compromises the effectiveness of many anthelmintics around the world. Thus, there is a need to discover new drugs, with unique modes of action, against parasites.MethodsHere, we synthesised and tested 74 selective estrogen receptor modulators (SERMs) for in vitro-activity on parasitic larvae of Haemonchus contortus (barber’s pole worm), one of the most important nematode pathogens of small ruminants (including sheep and goats) and a key representative of one of the largest groups of parasitic nematodes (the Strongylida) of animals. We also studied the morphology of treated and untreated larvae using scanning electron microscopy (SEM), and assessed the agonistic/antagonistic activity of SERMs in a human embryonic kidney cell line using a luciferase reporter assay system.ResultsWe identified three SERMs (one selenophene and two thiophene-core compounds) with potent inhibitory activities (at 3–25 μM) on the motility and development of parasitic stages of H. contortus. An SEM examination of treated H. contortus revealed considerable damage to the cuticle of fourth- but not exsheathed, third-stage larvae; this damage appeared to be consistent with that observed upon treatment with monepantel but not moxidectin (control compounds).ConclusionThe potency of the three SERMs compared favourably with commercially available anthelmintics, such that they warrant further assessment as nematocides. Future studies could focus on assessing the selectivity of these SERMs to parasites, characterising their target(s) and/or designing analogs that are parasite-specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1612-4) contains supplementary material, which is available to authorized users.

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A perspective on genomic-guided anthelmintic discovery and repurposing using Haemonchus contortus

Cited by 20 publications

References 71 publications

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Screening of the ‘Open Scaffolds’ collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Interactive online application for the prediction, ranking and prioritisation of drug targets in Schistosoma haematobium

Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

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