2. Academic Validation
  3. Identification of a family of species-selective complex I inhibitors as potential anthelmintics

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

  • Nat Commun. 2024 May 8;15(1):3367. doi: 10.1038/s41467-024-47331-3.
Taylor Davie 1 2,  Xènia Serrat 1 2,  Lea Imhof 3 4,  Jamie Snider 1 2,  Igor Štagljar 1 2 5 6,  Jennifer Keiser 3 4,  Hiroyuki Hirano 7,  Nobumoto Watanabe 7,  Hiroyuki Osada 7 8,  Andrew G Fraser 9 10
Affiliations

Affiliations

  • 1 The Donnelly Centre, University of Toronto, 160 College Street, Toronto, M5S 3E1, Canada.
  • 2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 3 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123, Allschwil, Switzerland.
  • 4 University of Basel, CH-4000, Basel, Switzerland.
  • 5 Mediterranean Institute for Life Sciences, Meštrovićevo Šetalište 45, HR-21000, Split, Croatia.
  • 6 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  • 7 Chemical Resource Development Research Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako Saitama, 351-0198, Japan.
  • 8 Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan.
  • 9 The Donnelly Centre, University of Toronto, 160 College Street, Toronto, M5S 3E1, Canada. andy.fraser@utoronto.ca.
  • 10 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. andy.fraser@utoronto.ca.
PMID: 38719808 DOI: 10.1038/s41467-024-47331-3
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.

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