Advances in the discovery and development of anthelmintics by harnessing natural product scaffolds

Herath, H. M. P. Dilrukshi; Taki, Aya C.; Sleebs, Brad E.; Hofmann, Andreas; Nguyen, Nghi; Preston, Sarah; Davis, Rohan A.; Jabbar, Abdul; Gasser, Robin B.

doi:10.1016/bs.apar.2020.10.002

Cited by 17 publications

(18 citation statements)

References 186 publications

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“…In 2015, we established a practical and inexpensive phenotypic assay (96-well format) for the in vitro-screening of compounds for activity against larval stages of H. contortus [ 30 ]. Since that time, this assay was used to screen 15,860 synthetic compounds as well as 10,760 natural products and extracts thereof to complete numerous projects (reviewed in [ 11 , 31 ]). The assay, which relies on video/image capture via microscopy, has performed well and has had significant advantages over conventional methods in that it relies on the use of L3s—which can be stored for many months at constant temperature in an incubator, substantially reducing experimental animal use; it is well-suited for the screening of hundreds or thousands of compounds for hit discovery, subsequent hit-to-lead optimisation, repurposing and development; it provides phenotypic (morphological) information and should have applicability to other socioeconomically important parasitic worms.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

et al. 2021

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Parasitic worms cause very significant diseases in animals and humans worldwide, and their control is critical to enhance health, well-being and productivity. Due to widespread drug resistance in many parasitic worms of animals globally, there is a major, continuing demand for the discovery and development of anthelmintic drugs for use to control these worms. Here, we established a practical, cost-effective and semi-automated high throughput screening (HTS) assay, which relies on the measurement of motility of larvae of the barber’s pole worm (Haemonchus contortus) using infrared light-interference. Using this assay, we screened 80,500 small molecules and achieved a hit rate of 0.05%. We identified three small molecules that reproducibly inhibited larval motility and/or development (IC50 values of ~4 to 41 µM). Future work will critically assess the potential of selected hits as candidates for subsequent optimisation or repurposing against parasitic nematodes. This HTS assay has a major advantage over most previous assays in that it achieves a ≥ 10-times higher throughput (i.e., 10,000 compounds per week), and is thus suited to the screening of libraries of tens of thousands to hundreds of thousands of compounds for subsequent hit-to-lead optimisation or effective repurposing and development. The current assay should be adaptable to many socioeconomically important parasitic nematodes, including those that cause neglected tropical diseases (NTDs). This aspect is of relevance, given the goals of the World Health Organization (WHO) Roadmap for NTDs 2021–2030, to develop more effective drugs and drug combinations to improve patient outcomes and circumvent the ineffectiveness of some current anthelmintic drugs and possible drug resistance.

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Section: Introductionmentioning

confidence: 99%

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

et al. 2021

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“…Enabling this focus are: (a) the accessibility of curated, drug-like extract-, fraction- and/or compound collections from natural sources; (b) the chemical diversity of natural products within these collections; (c) the availability of a phenotypic, whole-worm bioassays to screen these collections; and (d) the utility of advanced chromatographic, spectrometric and spectroscopic techniques for bioassay-guided fractionation and structural investigations (reviewed in [ 12 ]). This context has provided a sound basis for the identification and subsequent characterisation of anthelmintic molecules from natural sources.…”

Section: Introductionmentioning

confidence: 99%

High Throughput Screening of the NatureBank ‘Marine Collection’ in a Haemonchus Bioassay Identifies Anthelmintic Activity in Extracts from a Range of Sponges from Australian Waters

et al. 2021

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Widespread resistance in parasitic nematodes to most classes of anthelmintic drugs demands the discovery and development of novel compounds with distinct mechanisms of action to complement strategic or integrated parasite control programs. Products from nature—which assume a diverse ‘chemical space’—have significant potential as a source of anthelmintic compounds. In the present study, we screened a collection of extracts (n = 7616) derived from marine invertebrates sampled from Australian waters in a high throughput bioassay for in vitro anti-parasitic activity against the barber’s pole worm (Haemonchus contortus)—an economically important parasitic nematode of livestock animals. In this high throughput screen (HTS), we identified 58 active extracts that reduced larval motility by ≥70% (at 90 h), equating to an overall ‘hit rate’ of ~0.8%. Of these 58 extracts, 16 also inhibited larval development by ≥80% (at 168 h) and/or induced ‘non-wild-type’ (abnormal) larval phenotypes with reference to ‘wild-type’ (normal) larvae not exposed to extract (negative controls). Most active extracts (54 of 58) originated from sponges, three from chordates (tunicates) and one from a coral; these extracts represented 37 distinct species/taxa of 23 families. An analysis of samples by 1H NMR fingerprinting was utilised to dereplicate hits and to prioritise a set of 29 sponge samples for future chemical investigation. Overall, these results indicate that a range of sponge species from Australian waters represents a rich source of natural compounds with nematocidal or nematostatic properties. Our plan now is to focus on in-depth chemical investigations of the sample set prioritised herein.

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“…Anthelmintic drugs such as ivermectin (Campbell, 2012;Campbell et al, 1983) and benzimidazoles (Brown and Zweifel, 1961) are listed amongst the WHO Essential Drugs ("WHO model list of essential medicines," 2019) and have provided frontline treatment for these pathogens for decades. However, resistance is widespread in livestock (Herath et al, 2021;Kaplan and Vidyashankar, 2012;Sangster et al, 2018;Wolstenholme et al, 2004) and in certain regions efficacy for specific drugs has decreased in humans (Geerts and Gryseels, 2001;Kotze et al, 2020;Moser et al, 2019) and few classes of anthelmintics currently exist. There is thus an urgent need for new classes of anthelmintics to combat these major pathogens.…”

Section: Introductionmentioning

confidence: 99%

Identification of enzymes that are required for Rhodoquinone-dependent metabolism as targets for new species-specific inhibitors

Lautens

Serrat

et al. 2021

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Soil transmitted helminths (STHs) are major human pathogens that infect over a billion people. Resistance to current anthelmintics is rising and new drugs are needed. Here we combine multiple approaches to find druggable targets that are essential for RQ-dependent metabolism, an unusual form of anaerobic metabolism which STHs need to survive in their host. We identified 25 genes predicted to act in RQ-dependent metabolism from sensing hypoxia to RQ synthesis — this includes components of the kynurenine pathway we previously showed to be essential for RQ synthesis (Del Borrello et al., 2019). We found 9 genes to be required — since all have host orthologues, we used comparative genomics and structural modeling to identify those with helminth-specific active sites and found 4 such targets. These 4 high confidence targets open up the possibility of in silico screens to identify STH-specific inhibitors of these enzymes as new anthelmintics.

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Advances in the discovery and development of anthelmintics by harnessing natural product scaffolds

Cited by 17 publications

References 186 publications

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

High-Throughput Phenotypic Assay to Screen for Anthelmintic Activity on Haemonchus contortus

High Throughput Screening of the NatureBank ‘Marine Collection’ in a Haemonchus Bioassay Identifies Anthelmintic Activity in Extracts from a Range of Sponges from Australian Waters

Identification of enzymes that are required for Rhodoquinone-dependent metabolism as targets for new species-specific inhibitors

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