Target-based and whole-worm screening approaches to anthelmintic discovery

Abstract

Experimental approaches for identifying new anthelmintics include target-based and whole-worm screening methods. The former involves basic research into characterising and validating new targets, mostly proteins, followed by identification of inhibitors or agonists through the use of target-based screening assays and/or in silico drug design. The latter experimental approach uses whole-worm assays to identify anthelmintic agents with unknown modes of action, or where the primary interest lies in whether analogues are able to kill (or disable) worms rather than in measuring their direct impact on their likely target. This paper focuses initially on the intestine and external layers of nematodes as potential drug targets. Specific anthelmintic agents targeting either tissue are discussed to illustrate the impact of disruption to these structures. In both cases, the activity of these agents against insects was known, and activity against nematodes was identified using whole worm screening assays. Recent literature identifying ecdysone signalling pathway receptors in nematodes is then used to provide an example of basic research into a specific target that may lead to the development of high-throughput target-based drug screening assays. Finally, the role of whole-worm screening approaches versus target-based screening is discussed briefly.