The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains.

Sara Christina Stolze, Edgar Deu, Farnusch Kaschani, Nan Li, Bogdan I Florea, Kerstin H Richau, Tom Colby, Renier A L van der Hoorn, Hermen S Overkleeft, Matthew Bogyo, Markus Kaiser

Chemistry & biology 2012 Dec 21

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The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Sara Christina Stolze, Edgar Deu, Farnusch Kaschani, Nan Li, Bogdan I Florea, Kerstin H Richau, Tom Colby, Renier A L van der Hoorn, Hermen S Overkleeft, Matthew Bogyo, Markus Kaiser. The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains. Chemistry & biology. 2012 Dec 21;19(12):1546-55