Identification of a family of species-selective complex I inhibitors as potential anthelmintics.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 May 2024
08 May 2024
Historique:
received:
22
08
2023
accepted:
28
03
2024
medline:
9
5
2024
pubmed:
9
5
2024
entrez:
8
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38719808
doi: 10.1038/s41467-024-47331-3
pii: 10.1038/s41467-024-47331-3
doi:
Substances chimiques
Anthelmintics
0
Electron Transport Complex I
EC 7.1.1.2
Benzimidazoles
0
rhodoquinone
JVC3PUU81F
Quinones
0
Biological Products
0
Ubiquinone
1339-63-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3367Informations de copyright
© 2024. The Author(s).
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