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  • The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.

The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.

Cell chemical biology (2020-01-25)
Euna Yoo, Christopher J Schulze, Barbara H Stokes, Ouma Onguka, Tomas Yeo, Sachel Mok, Nina F Gnädig, Yani Zhou, Kenji Kurita, Ian T Foe, Stephanie M Terrell, Michael J Boucher, Piotr Cieplak, Krittikorn Kumpornsin, Marcus C S Lee, Roger G Linington, Jonathan Z Long, Anne-Catrin Uhlemann, Eranthie Weerapana, David A Fidock, Matthew Bogyo
ABSTRACT

Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

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Sigma-Aldrich
JW651, ≥98% (HPLC)