Ion Channels and Drug Transporters as Targets for Anthelmintics

Abstract

Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

Polymorphism in ion channel genes of Dirofilaria immitis : Relevant knowledge for future anthelmintic drug design

“…For the animal health sector, there has been an increased focus on the discovery of new drugs for canine heartworm (Geary et al., 2015). In the context of discovering new anthelmintics, it is of interest that ion channels in the neuromuscular systems of nematodes have been successful drug targets for many of the anthelmintics discovered in the past, and remain targets of choice for discovery of new anthelmintics (Wolstenholme, 2011, Greenberg, 2014). …”

“…The neuromuscular system of D. immitis shows great potential as a drug target; nematodes have well-developed neuromuscular systems that control motility, navigation, feeding, mating and responses to environmental cues, which are essential for their survival, development and reproduction (White et al., 1986, Perry et al., 2004, Greenberg, 2014). Interference with any of these activities can paralyse, kill or stop reproduction in the parasite (Greenberg, 2014).…”

“…Interference with any of these activities can paralyse, kill or stop reproduction in the parasite (Greenberg, 2014). Ion channels and associated receptors that underlie neuromuscular systems are targets for a wide variety of naturally occurring toxins and synthetic compounds (Camerino et al., 2007).…”

“…Ion channels of nematodes may be classified by the type of ions that are allowed to pass through them (e.g. cations (Na + , K + and Ca ++ ) or anions (Cl − )), and by the type of gating: voltage gated (sodium, calcium or potassium channels) or ligand gated (in which the ligand may be an amino-acid such as glutamate, ɤ-amino butyric acid (GABA), or a biogenic amine such as serotonin, tyramine or dopamine) (Wolstenholme, 2011, Greenberg, 2014). Among the ligand-gated ion channels (LGICs), the cysteine-loop (cys-loop) superfamily includes cation-permeable acetylcholine receptors as well as anion-selective channels gated by GABA, glutamate, 5-hydroxytryptamine, dopamine or tyramine (Raymond and Sattelle, 2002, Hobert, 2013, Ringstad et al., 2009, Lees et al., 2012).…”

Functional genomics in Brugia malayi reveal diverse muscle nAChRs and differences between cholinergic anthelmintics

“…The neuromuscular systems of nematodes, which control motility and support feeding, growth, and reproduction, are governed by significant parts of their gene pools (8,9). Their neuromuscular systems are unlike those of vertebrates because nematode muscles send processes to the motor neurons to form synapses, rather than the other way around.…”