Whole-organism phenotypic screening methods used in early-phase anthelmintic drug discovery

Herath, H. M. P. Dilrukshi; Taki, Aya C.; Rostami, Ali; Jabbar, Abdul; Keiser, Jennifer; Geary, Timothy G.; Gasser, Robin B.

doi:10.1016/j.biotechadv.2022.107937

Cited by 28 publications

(18 citation statements)

References 118 publications

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“…[26]). At the present time, the small number of classes of anthelmintics available [27,28] and the problem of widespread anthelmintic resistance [29] demand concerted efforts to discover new anthelmintic drugs with novel mechanisms/modes of action. Thus, some of the proteins identified here in the adult stage of H. contortus (which is the blood-feeding and pathogenic stage of the nematode) could be promising target candidates to evaluate, as the druggability of protein kinases is well-established [30], with > 70 kinase inhibitors on the market and > 150 in development.…”

Section: Discussionmentioning

confidence: 99%

Repurposing of a human antibody-based microarray to explore conserved components of the signalome of the parasitic nematode Haemonchus contortus

Adderley

Wang

et al. 2022

Parasites Vectors

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Background Gaining insight into molecular signalling pathways of socioeconomically important parasitic nematodes has implications for understanding their molecular biology and for developing novel anthelmintic interventions. Methods Here, we evaluated the use of a human antibody-based microarray to explore conserved elements of the signalome in the barber’s pole worm Haemonchus contortus. To do this, we prepared extracts from mixed-sex (female and male) adult worms and third-stage larvae (L3s), incubated these extracts on the antibody microarray and then measured the amounts of antibody-bound proteins (‘signal intensity’). Results In total, 878 signals were classified into two distinct categories: signals that were higher for adults than for larvae of H. contortus (n = 376), and signals that were higher for larvae than for adults of this species (n = 502). Following a data-filtering step, high confidence (‘specific’) signals were obtained for subsequent analyses. In total, 39 pan-specific signals (linked to antibodies that recognise target proteins irrespective of their phosphorylation status) and 65 phosphorylation-specific signals were higher in the adult stage, and 82 pan-specific signals and 183 phosphorylation-specific signals were higher in L3s. Thus, notably more signals were higher in L3s than in the adult worms. Using publicly available information, we then inferred H. contortus proteins that were detected (with high confidence) by specific antibodies directed against human homologues, and revealed relatively high structural conservation between the two species, with some variability for select proteins. We also in silico-matched 763 compound structures (listed in the DrugBank and Kinase SARfari public databases) to four H. contortus proteins (designated HCON_00005760, HCON_00079680, HCON_00013590 and HCON_00105100). Conclusions We conclude that the present antibody-based microarray provides a useful tool for comparative analyses of signalling pathways between/among developmental stages and/or species, as well as opportunities to explore nematocidal target candidates in H. contortus and related parasites. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Repurposing of a human antibody-based microarray to explore conserved components of the signalome of the parasitic nematode Haemonchus contortus

Adderley

Wang

et al. 2022

Parasites Vectors

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“…Some recent anthelmintic drug discovery efforts (reviewed by Herath et al, 2022 ) have been centred around two nematodes – the strongylid H. contortus and the free-living Caenorhabditis elegans . Both of these species represent useful models for anthelmintic drug discovery, because they can be readily maintained and produced in a laboratory setting and are both related to numerous socioeconomically important nematodes (clade V; order Strongylida) of animals and humans.…”

Section: Introductionmentioning

confidence: 99%

Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans

Shanley,

Taki,

Nguyen

et al. 2024

International Journal for Parasitology: Drugs and Drug Resistan

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“…Our focus has been on screening a range of curated compound libraries using phenotypic assays for the parasitic nematode Haemonchus contortus-called the barber's pole worm (Jiao et al, 2020;Herath et al, 2021;Herath et al, 2022). We employ this worm species, because 1) it is a highly significant, pathogenic nematode with a high reproductive index, and can be readily maintained in a laboratory environment; 2) it represents one of the largest groups (clade V) of socioeconomically relevant nematodes of animals, including a range of species parasitic in humans; 3) it is relatively closely related to Caenorhabditis elegans (also clade V)-a free-living nematode-which is one of the best understood multicellular organisms (Holden-Dye and Walker, 2014;Hahnel et al, 2020) and for which extensive biological, biochemical, molecular, genetic and genomic resources exist (Harris et al, 2019;Davis et al, 2022); and 4) it now assumes 'model organism' status (Doyle et al, 2020) due to the availability of extensive genomic, transcriptomic, proteomic and lipidomic data sets and resources for this parasitic nematode (Laing et al, 2013;Schwarz et al, 2013;Gasser et al, 2016;Ma et al, 2018;Wang et al, 2018;Wang et al, 2019a;Wang et al, 2019b;Ma et al, 2020a;Wang et al, 2020a;Ma et al, 2020b;Wang et al, 2020b;Doyle et al, 2020;.…”

Section: Introductionmentioning

confidence: 99%

Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868

et al. 2022

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Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber’s pole worm, and in other socioeconomically important parasitic nematodes. The “hit-to-target” workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets.

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Whole-organism phenotypic screening methods used in early-phase anthelmintic drug discovery

Cited by 28 publications

References 118 publications

Repurposing of a human antibody-based microarray to explore conserved components of the signalome of the parasitic nematode Haemonchus contortus

Repurposing of a human antibody-based microarray to explore conserved components of the signalome of the parasitic nematode Haemonchus contortus

Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans

Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868

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