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Prodrugging fungicidal amphotericin B significantly decreases its toxic effects
O. Štěpánek, M. Parigger, E. Procházková, A. Čmoková, M. Kolařík, H. Dračínská, V. Černá, K. Kalíková, V. Grobárová, J. Černý, J. Scheler, G. Schweiger, U. Binder, O. Baszczyňski
European journal of medicinal chemistry.
2025 ;
283 (-) :
117157.
[pub] 20241209
Language English Country France
Document type Journal Article
Persistent link
https://www.medvik.cz/link/bmc25009941
- MeSH
- Amphotericin B * pharmacology MeSH
- Antifungal Agents * pharmacology chemistry chemical synthesis MeSH
- Aspergillus drug effects MeSH
- Candida drug effects MeSH
- Larva drug effects MeSH
- Microbial Sensitivity Tests * MeSH
- Molecular Structure MeSH
- Moths drug effects MeSH
- Prodrugs * pharmacology chemistry chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design.
References provided by Crossref.org
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