Potential nematicides identified through targeted in vivo screening of a 5-HT-gated chloride channel, MOD-1

New approaches to mitigate the reduction of crop yields by plant parasitic nematodes are needed in the face of increasing concerns of the impact of nematicides on precious ecosystems. One approach is to target receptors in the parasitic nematode that are vital for their survival that less widely expressed in non-target organisms. Nematodes express a phylogenetically restricted 5-HT-gated chloride channel, MOD-1, activation of which causes paralysis in Caenorhabditis elegans. We show that MOD-1 is expressed in the motor nervous system of the plant parasitic nematode Globodera pallida and its functional characterisation is validated by 5-HT activation when reconstituted in Xenopus laevis oocytes. To evaluate MOD-1 as a nematicide target we utilised a previously described platform called PhaGeM4 for PharmacoGenetic targeting of M4 neurone in which MOD-1 is expressed in transgenic C. elegans and nematode development in the face of MOD-1 chemical modulation is tracked. We screened Pathogen Box, a chemical library of 400 diverse drug-like molecules, using PhaGeM4. This identified 10 putative hits for C. elegans MOD-1. These hits were pursued through a sequential, iterative pipeline encompassing mod-1 dependent C. elegans motility and G.pallida motility assays in combination with pharmacological interrogation of G. pallida mod-1 in PhaGeM4. This approach highlights 3 compounds with a mod-1 dependent action (quipazine, our benchmark compound; MMV687251, a vancomycin-like compound; MMV688774, an antifungal with common name posaconazole) and one compound that acts through an undetermined target (MMV002816, also known as the antifilarial drug, diethylcarbamazine). Each of these compounds had a significant inhibitory effect on G. pallida J2 root invasion. Overall, this lends confidence that the PhaGeM4 screening platform can delivery new chemical leads for crop protection and highlights four new chemistries of interest. More generally, this approach could be applied to other ligand-gated ion channels of interest as targets.