Document Detail

The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains.
MedLine Citation:
PMID:  23261598     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biology     Volume:  19     ISSN:  1879-1301     ISO Abbreviation:  Chem. Biol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-24     Completed Date:  2013-06-04     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1546-55     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Antimalarials / chemistry,  pharmacology*,  therapeutic use
Cysteine Endopeptidases / metabolism*
Enzyme Inhibitors / chemistry,  pharmacology,  therapeutic use
Erythrocytes / parasitology*
Hemoglobins / metabolism
Host-Parasite Interactions / drug effects
Malaria, Falciparum / drug therapy*,  parasitology
Models, Molecular
Peptides / chemistry,  pharmacology*,  therapeutic use
Plasmodium falciparum / drug effects,  enzymology*,  physiology
Grant Support
Reg. No./Substance:
0/Antimalarials; 0/Enzyme Inhibitors; 0/Hemoglobins; 0/Peptides; 0/gallinamide A; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/falcipain

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