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Abstract
Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.
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Details
1 University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)
2 Université de Paris, CNRS, Programme Équipe Labellisée Ligue Contre Le Cancer, Institut Jacques Monod, UMR7592, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602)
3 University of California San Francisco, Cardiovascular Research Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
4 University of California San Francisco, Cardiovascular Research Institute, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Department of Cellular and Molecular Pharmacology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
5 UNC Eshelman, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208)
6 University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, The Donnelly Centre for Cellular and Biomolecular Research, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Pharmacology and Toxicology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)