The antimalarial natural product salinipostin A identifies essential α/β serine hydrolases involved in lipid metabolism in P. falciparum parasites

SUMMARYSalinipostin A (Sal A) is a potent antimalarial 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 high 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 and produces disorganized and stalled schizonts similar to Sal A. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a 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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The Antimalarial Natural Product Salinipostin a Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. Falciparum Parasites

SSRN Electronic Journal ◽

10.2139/ssrn.3479442 ◽

2019 ◽

Author(s):

Euna Yoo ◽

Christopher J. Schulze ◽

Barbara H. Stokes ◽

Ouma Onguka ◽

Tomas Yeo ◽

...

Keyword(s):

Lipid Metabolism ◽

Natural Product ◽

Serine Hydrolases

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The Bis(Indolyl)Imidazole Alkaloid Nortopsentin A Exhibits Antiplasmodial Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02091-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2362-2364 ◽

Cited By ~ 18

Author(s):

Stephenie Alvarado ◽

Bracken F. Roberts ◽

Amy E. Wright ◽

Debopam Chakrabarti

Keyword(s):

Plasmodium Falciparum ◽

Natural Product ◽

Parasite Growth ◽

Sybr Green I ◽

Antiplasmodial Activity ◽

Marine Natural Product ◽

Trophozoite Stage ◽

Content Type ◽

First Report ◽

Potent Inhibition

ABSTRACTA library of enriched marine natural product fractions was screened for their antiplasmodial activity using a SYBR green I fluorescence-based assay. Fractions derived from a sponge of the genusSpongosoritesexhibited potent inhibition ofPlasmodium falciparumgrowth. This genus of sponge has been reported to contain the nortopsentin and topsentin class of bis-indole imidazole alkaloids. This is the first report of nortopsentin A inhibiting parasite growth at the trophozoite stage at submicromolar 50% inhibitory concentrations (IC50).

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(+)-Discodermolide: A Marine Natural Product Against Cancer

The Scientific World JOURNAL ◽

10.1100/tsw.2004.96 ◽

2004 ◽

Vol 4 ◽

pp. 415-436 ◽

Cited By ~ 14

Author(s):

Marcus Viníus Nora De Souza

Keyword(s):

Drug Resistance ◽

Total Synthesis ◽

Natural Product ◽

Multiple Drug Resistance ◽

Marine Natural Product ◽

Cellular Biology ◽

Cancer Drug ◽

Multiple Drug ◽

Important Target ◽

Nanomolar Range

(+)-Discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta. It attacks cancer cells in a similar way to the successful cancer drug Taxol® that has become the best-selling anticancer drug in history. Taxol is also the first natural product described that stabilizes the microtubules involved in many aspects of cellular biology and that represent an important target of anticancer chemotherapeutics. However, (+)-discodermolide appears to be far more potent than Taxol® against tumors that have developed multiple-drug resistance, with an IC50in the low nanomolar range. Due to these excellent results, this natural product was licensed to Novartis Pharmaceutical Corporation in early 1998. The present review covers the history, biological activity, total synthesis, and synthetic analogs of (+)-discodermolide.

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