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Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2024 Aug 10. Date of Electronic Publication: 2024 Aug 10. - Publication Year :
- 2024
- Publisher :
- Ahead of Print
-
Abstract
- Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. Our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are promising, synthetically tractable antimalarials.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2451-9448
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 39137783
- Full Text :
- https://doi.org/10.1016/j.chembiol.2024.07.006