Identification of a family of species-selective complex I inhibitors as potential anthelmintics

Taylor Davie, Xènia Serrat, Lea Imhof, Jamie Snider, Igor Štagljar, Jennifer Keiser, Hiroyuki Hirano, Nobumoto Watanabe, Hiroyuki Osada and Andrew G. Fraser ()
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Taylor Davie: University of Toronto
Xènia Serrat: University of Toronto
Lea Imhof: Swiss Tropical and Public Health Institute, Kreuzstrasse 2
Jamie Snider: University of Toronto
Igor Štagljar: University of Toronto
Jennifer Keiser: Swiss Tropical and Public Health Institute, Kreuzstrasse 2
Hiroyuki Hirano: RIKEN Center for Sustainable Resource Science
Nobumoto Watanabe: RIKEN Center for Sustainable Resource Science
Hiroyuki Osada: RIKEN Center for Sustainable Resource Science
Andrew G. Fraser: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.

Date: 2024
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DOI: 10.1038/s41467-024-47331-3

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