Automated Imaging and other developments in whole‐organism anthelmintic screening

Abstract

Helminth infections still represent a huge public health problem throughout the developing world and in the absence of vaccines control is based on periodic mass drug administration. Poor efficacy of some anthelmintics and concerns about emergence of drug resistance has highlighted the need for new drug discovery. Most current anthelmintics were discovered through in vivo screening of selected compounds in animal models but recent approaches have shifted towards screening for activity against adult or larval stages in vitro. Larvae are normally available in greater numbers than adults, can often be produced in vitro and are small enough for microplate assays. However, the manual visualization of drug effects in vitro is subjective, laborious and slow. This can be overcome by application of automated readouts including high-content imaging. Incorporated into robotically controlled HTS platforms such methods allow the very large compound collections being made available by the pharmaceutical industry or academic organizations to be screened against helminths for the first time, invigorating the drug discovery pipeline. Here, we review the status of whole-organism screens based on in vitro activity against living worms and highlight the recent progress towards automated image-based readouts.

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

“…Importantly, the integrated use of advanced genomic, transcriptomic, proteomic and bioinformatic methods will likely support investigations of the structures and functions of key molecules essential to the development, reproduction and survival of parasitic nematodes, and should pave the way for the prediction, prioritization and/or design of small molecular inhibitors as new nematocides. To this end, recently developed drug-screening assays that use the parasitic stages of worms and have medium-throughput (reviewed by Paveley and Bickle, 2013;Preston et al, 2015) should be adaptable to various parasites of socioeconomic importance, including those causing neglected tropical diseases. We consider this focus to be of considerable relevance, given the need to meet the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration).…”

“…This assay achieves high levels of repeatability and low levels of intra-and inter-assay variabilities , and has significant advantages over conventional methods (such as larval development, motility and migration inhibition methods; cf. Le Jambre, 1976; Martin and Le Jambre, 1979;Dobson et al, 1986;Kotze et al, 2006;Demeler et al, 2010), particularly in terms of ease of use, accuracy of results, throughput, time and cost, and compares very favourably with other assays developed for parasitic worms (e.g., Smout et al, 2010;Marcellino et al, 2012;Paveley et al, 2012;Paveley and Bickle, 2013;Hurst et al, 2014;Storey et al, 2014).…”

Current Screening Methodologies in Drug Discovery for Selected Human Diseases

“…The larvae of helminths are normally available in greater numbers than adults and are small enough for microplate assays. These characteristics, together with the implemented high-content imaging techniques, have made it possible to use large compound collections to be screened against helminths, revitalizing the drug discovery pipeline [95]. Both light-field and fluorescent-based assays have been performed for testing the viability of the parasites after drug treatment.…”

QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni

“…29 Whole-organism antihelminthic screens employing the HCS approach have already proved useful for the larval stage of S. mansoni . 30 …”