Ligand‐Gated Ion Channels as Targets for Anthelmintic Drugs: Past, Current, and Future Perspectives

Abstract

Ligand-gated ion channels (LGIC) are targets for anthelmintic drugs used in human health and veterinary applications. Given the diverse physiological roles of LGICs in neuromuscular function, the nervous system, and elsewhere, it is not surprising that random chemical screening programs often identify drug candidates targeting this superfamily of transmembrane proteins. Such leads provide the basis for further chemical optimization, resulting in important commercial products. Currently, members of three LGIC families are known to be targeted by anthelmintics. These include the nicotinic acetylcholine receptors gating cation channels, glutamate-gated chloride channels, and g-aminobutyric acid-gated chloride channels. The recent impact of genomics on model invertebrates and parasitic species has been farreaching, leading to the description of new helminth LGIC families. Among the current challenges for anthelmintic drug discovery are the assessment of newly discovered LGICs as viable targets (validation) and circumventing resistance when exploring further the well-established targets. Recombinant expression of helminth LGICs is not always straightforward. However, new developments in the understanding of LGIC chaperones and automated screening technologies may hold promise for target validation and chemical library screening on whole organisms or ex vivo preparations. Here, we describe LGIC targets for the current anthelmintics of commercial importance and discuss the potential impact of that knowledge on screening for new compounds. In addition, we discuss some new technologies for anthelmintic drug hunting, aimed at the discovery of novel treatments to control veterinary parasites and some neglected human diseases.