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Sci Rep. 2019 Jun 24;9(1):9085. doi: 10.1038/s41598-019-45548-7.

Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, Missouri, 63108, USA.
2
University of Massachusetts Medical School, Suite 219 Biotech 2, 373 Plantation St., Worcester, Massachusetts, 01605, USA.
3
UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53792, USA.
4
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660S. Euclid Ave., Box 8231, St. Louis, Missouri, 63110, USA.
5
Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th St, San Francisco, California, 94158, USA.
6
Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Ross Hall, Room 521, 2300 I Street, NW, Washington, DC, 20037, USA.
7
McDonnell Genome Institute, Washington University School of Medicine, 4444 Forest Park Ave, St. Louis, Missouri, 63108, USA. mmitreva@wustl.edu.
8
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 4523 Clayton Ave., CB 8051, St. Louis, MO, 63110, USA. mmitreva@wustl.edu.

Abstract

Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm parasites. Here, we performed omics-driven knowledge-based identification of chokepoint enzymes as anthelmintic targets. We prioritized 10 of 186 phylogenetically conserved chokepoint enzymes and undertook a target class repurposing approach to test and identify new small molecules with broad spectrum anthelmintic activity. First, we identified and tested 94 commercially available compounds using an in vitro phenotypic assay, and discovered 11 hits that inhibited nematode motility. Based on these findings, we performed chemogenomic screening and tested 32 additional compounds, identifying 6 more active hits. Overall, 6 intestinal (single-species), 5 potential pan-intestinal (whipworm and hookworm) and 6 pan-Phylum Nematoda (intestinal and filarial species) small molecule inhibitors were identified, including multiple azoles, Tadalafil and Torin-1. The active hit compounds targeted three different target classes in humans, which are involved in various pathways, including carbohydrate, amino acid and nucleotide metabolism. Last, using representative inhibitors from each target class, we demonstrated in vivo efficacy characterized by negative effects on parasite fecundity in hamsters infected with hookworms.

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