Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.
Cell Chem Biol
; 2024 Aug 10.
Article
em En
| MEDLINE
| ID: mdl-39137783
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2024
Tipo de documento:
Article