| The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains. | |
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MedLine Citation:
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PMID: 23261598 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article |
Journal Detail:
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Title: Chemistry & biology Volume: 19 ISSN: 1879-1301 ISO Abbreviation: Chem. Biol. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9500160 Medline TA: Chem Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1546-55 Citation Subset: IM |
Copyright Information:
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Copyright © 2012 Elsevier Ltd. All rights reserved. |
Affiliation:
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Zentrum für Medizinische Biotechnologie, Fakultät für Biologie, Universität Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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