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Chem Biol. 2012 Dec 21;19(12):1546-55. doi: 10.1016/j.chembiol.2012.09.020.

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

Author information

1
Zentrum für Medizinische Biotechnologie, Fakultät für Biologie, Universität Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany.

Abstract

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.

PMID:
23261598
PMCID:
PMC3601557
DOI:
10.1016/j.chembiol.2012.09.020
[Indexed for MEDLINE]
Free PMC Article

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