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

2020; Elsevier BV; Volume: 27; Issue: 2 Linguagem: Inglês

10.1016/j.chembiol.2020.01.001

2451-9456

Euna Yoo, Christopher J. Schulze, Barbara H. Stokes, Ouma Onguka, Tomas Yeo, Sachel Mok, Nina F. Gnädig, Yani Zhou, Kenji L. Kurita, Ian T. Foe, Stephanie M. Terrell, Michael J. Boucher, Piotr Cieplak, Krittikorn Kümpornsin, Lee M, Roger G. Linington, Jonathan Z. Long, Anne‐Catrin Uhlemann, Eranthie Weerapana, David A. Fidock, Matthew Bogyo,

Synthesis and Catalytic Reactions

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.