Cancer Institute A national cancer institute
designated cancer center

Matthew Bogyo

Publication Details

  • The Antimalarial Natural Product Symplostatin 4 Is a Nanomolar Inhibitor of the Food Vacuole Falcipains CHEMISTRY & BIOLOGY Stolze, S. C., Deu, E., Kaschani, F., Li, N., Florea, B. I., Richau, K. H., Colby, T., van der Hoom, R. A., Overkleeft, H. S., Bogyo, M., Kaiser, M. 2012; 19 (12): 1546-1555

    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.

    View details for DOI 10.1016/j.chembiol.2012.09.020

    View details for Web of Science ID 000313087300008

    View details for PubMedID 23261598

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