Low cost whole-organism screening of compounds for anthelmintic activity. Issue 5 (April 2015)

• Record Type: Journal Article
• Authors: Preston, Sarah; Jabbar, Abdul; Nowell, Cameron; Joachim, Anja; Ruttkowski, Bärbel; Baell, Jonathan; Cardno, Tony; Korhonen, Pasi K.; Piedrafita, David; Ansell, Brendan R.E.; Jex, Aaron R.; Hofmann, Andreas; Gasser, Robin B.
• Is Part Of: International journal for parasitology. Volume 45:Issue 5(2015)
• Page Start: 333
• Page End: 343
• Publication Date: 2015-04
• Subjects: Haemonchus contortus -- Anthelmintic screening -- Motility assay -- Automated imaging analysis -- Kinase inhibitor -- Biphenyl amide -- Pyrazolo[1, 5-α]pyridine; Parasitology -- Periodicals; Parasitology -- Periodicals; Parasitologie -- Périodiques; Parasitology; Periodicals; Electronic journals; 571.999
• DOI: 10.1016/j.ijpara.2015.01.007
• Languages: English
• ISSNs: 0020-7519

Abstract

Graphical abstract: Highlights: Whole-organism screening of compounds for anthelmintic activity using automated image-based analysis of worm motility. A compound library of 522 kinases inhibitors was screened against Haemonchus contortus . Two of these compounds inhibited larval motility, development and growth. This phenotypic screening method has broad applicability to a range of parasites. Abstract: 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 IC50 s of 14–47 μM. 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 (http://unitingtocombatntds.org/resource/london-declaration ) through the rapid and efficient repurposing of compounds in public–private partnerships.