期刊
CHEMISTRY & BIOLOGY
卷 19, 期 12, 页码 1546-1555出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2012.09.020
关键词
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资金
- Max Planck Society
- Deutsche Forschungsgemeinschaft [HO 3983/4-1]
- ERC [258413]
- NIH [R01EB005011, R01AI078947]
- European Research Council (ERC) [258413] Funding Source: European Research Council (ERC)
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.
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