Roy, Peter et al. (2021) International Worm Meeting "A C. elegans Motor-Centric Screening Pipeline Yields Novel and Selective Nematicidal Scaffolds"

Stagljar, Igor, Pyche, Jacob, Yip, Christopher, Gilleard, John, Snider, Jamie, Zasada, Inga, Harrington, Sean, Lautens, Mark, Guiliani, Maximillano, Dowling, James, Jiang, Yan, Wong, Vicotria, Choo, Ken-Loon, Palmeira, Bruna, Cutler, Sean, Volpatti, Jonathan, Redman, Elizabeth, Au, Aaron, Haeberli, Cecile, Knox, Jessica, Kitner, Megan, Roy, Peter, Keiser, Jennifer, Vaidya, Aditya, Kim, Yong-Hyun, Burns, Andrew

[International Worm Meeting, 2021]

Nematode parasites of humans, livestock and crops pose a significant burden to human health and welfare. Alarmingly, our arsenal of effective nematocidal compounds is being depleted. Parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides used for crop protection have been restricted or banned because of poor phylum-selectivity. Here, we present our C. elegans-based discovery pipeline focused on lethal molecules that also induce motor defects. This pipeline yielded multiple new and selective nematicidal small molecule scaffolds (i.e., structurally-related families of molecules). We show that one of these scaffolds, tentatively called the APPs, stimulates neurotransmitter release and immobilizes larvae of multiple nematode parasites of plants and mammals in vitro. At similar concentrations, APP-1 does little to model flies, fish, plants or human cells. Forward genetic screens of 100,000s of mutant genomes failed to yield resistant animals that resist the lethal effects of APP-1, suggesting that resistance to the APPs in the field may not be easily generated. Hence, the APPs represent a novel, selective and potentially useful addition to our nematocidal armament.