Galectin-11 : A novel host mediator targeting specific stages of the gastrointestinal nematode parasite, Haemonchus contortus
- Authors: Preston, Sarah , Beddoe, Travis , Walkden-Brown, Stephen , Meeusen, Els , Piedrafita, David
- Date: 2015
- Type: Text , Journal article
- Relation: International Journal for Parasitology Vol. 45, no. 12 (2015), p. 791-796
- Full Text: false
- Reviewed:
- Description: Galectin-11 is released from epithelial cells of the gastrointestinal tract, specifically following infection with gastrointestinal parasites including the highly pathogenic nematode, Haemonchus contortus. The function(s) of galectin-11 are currently unknown but seem to be associated with the development of immunity by the host. The aim of the present study was to examine the interaction of galectin-11 with the different parasitic life cycle stages of H. contortus and determine any effects on parasite development. The results of this study showed that galectin-11 binds to the surface of the L4 and adult stages of the parasite but not to the exsheathed L3 stage. In addition, at a lower concentration, binding to the L4 was specifically localised to the pharynx region. Subsequent in vitro assays demonstrated significant inhibition of larval growth and development in the presence of recombinant galectin-11. These results indicate, to our knowledge for the first time, a functional role for galectin-11 in gastrointestinal nematode infection of ruminants and a mechanism of action of galectin-11, targeting the development and growth of the L4 and possibly the adult parasite stage. © 2015 .
Metabolic profiling and in vitro assessment of anthelmintic fractions of Picria fel-terrae Lour
- Authors: Kumarasingha, Rasika , Karpe, Avinash , Preston, Sarah , Yeo, Tiong-Chia , Lim, Diana , Tu, Chu-Lee , Luu, Jennii , Simpson, Kaylene , Shaw, Jillian , Gasser, Robin , Beale, David , Morrison, Paul , Palombo, Enzo , Boag, Peter
- Date: 2016
- Type: Text , Journal article
- Relation: International Journal for Parasitology: Drugs and Drug Resistance Vol. 6, no. 3 (2016), p. 171-178
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- Description: Anthelmintic resistance is widespread in gastrointestinal nematode populations, such that there is a consistent need to search for new anthelmintics. However, the cost of screening for new compounds is high and has a very low success rate. Using the knowledge of traditional healers from Borneo Rainforests (Sarawak, Malaysia), we have previously shown that some traditional medicinal plants are a rich source of potential new anthelmintic drug candidates. In this study, Picria fel-terrae Lour. plant extract, which has previously shown promising anthelmintic activities, was fractionated via the use of a solid phase extraction cartridge and each isolated fraction was then tested on free-living nematode Caenorhabditis elegans and the parasitic nematode Haemonchus contortus. We found that a single fraction was enriched for nematocidal activity, killing ≥90% of C. elegans adults and inhibiting the motility of exsheathed L3 of H. contortus, while having minimal cytotoxic activity in mammalian cell culture. Metabolic profiling and chemometric analysis of the effective fraction indicated medium chained fatty acids and phenolic acids were highly represented. Image 1 •Chemical fractionation of Picria fel-terrae Lour. plant extract.•Anthelmintic activity against Caenorhabditis elegans and Haemonchus contortus.•Metabolic profiling and chemometric analysis of active fraction.•Active fraction has minimal mammalian cytotoxicity.
Low cost whole-organism screening of compounds for anthelmintic activity
- Authors: Preston, Sarah , Jabbar, Abdul , Nowell, Cameron , Joachim, Anja , Ruttkowski, Barbel , Baell, Jonathan , Cardno, Tony , Korhonen, Pasi , Piedrafita, David , Ansell, Brendan , Jex, Aaron , Hofmann, Andreas , Gasser, Robin
- Date: 2015
- Type: Text , Journal article
- Relation: International Journal for Parasitology Vol. 45, no. 5 (2015), p. 333-343
- Full Text: false
- Reviewed:
- Description: Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-α]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47μM. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (