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Cell Chem Biol. 2020 Feb 20;27(2):143-157.e5. doi: 10.1016/j.chembiol.2020.01.001. Epub 2020 Jan 23.

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

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
3
Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
4
Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
6
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Infectious & Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
8
Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
9
Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
10
Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
11
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mbogyo@stanford.edu.

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.

KEYWORDS:

Plasmodium falciparum; Salinipostin A; activity-based probes; chemical proteomics; lipid metabolism; malaria; natural products; serine hydrolases

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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