Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets

ABSTRACT: Malaria, caused by Plasmodium falciparum, remains a significant health burden. The barrier for developing anti-malarial 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 with 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 anti-parasitic potencies which enabled the identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. In addition, like SalA, 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 a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum (isolate 3d7)

SUBMITTER: Daniel Abegg  

LAB HEAD: Alexander Adibekian

PROVIDER: PXD051499 | Pride | 2024-07-15

REPOSITORIES: Pride