Document Detail

Characterization of Plasmodium liver stage inhibition by halofuginone.
MedLine Citation:
PMID:  22438279     Owner:  NLM     Status:  MEDLINE    
Malaria is a devastating parasitic disease that afflicts one-third of the world's population. Antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. Most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the Plasmodium parasite's life cycle within the human host. The identification of inhibitors active against liver-stage malaria would benefit the development of chemical probes to elucidate the poorly understood biology of this phase of the parasite life cycle and could provide agents to prevent and eliminate the disease. Herein we report the development of a live-cell parasite traversal assay in 384-well format amenable to high-throughput screening that exploits the wounding of liver cells by the parasite. This method identifies small molecules that may inhibit the parasite's actin-myosin motor system. The traversal assay, in addition to established methods, was used to evaluate the activity of halofuginone, a synthetic halogenated derivative of the natural alkaloid febrifugine, against liver-stage Plasmodium berghei parasites. Halofuginone was found to inhibit P. berghei sporozoite load in HepG2 cells with an IC(50) value of 17 nM. While the compound does not affect parasite traversal through human liver cells, an inhibition time course assay indicates that it affects essential processes in both early- and late-stage parasite development.
Emily R Derbyshire; Ralph Mazitschek; Jon Clardy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-21
Journal Detail:
Title:  ChemMedChem     Volume:  7     ISSN:  1860-7187     ISO Abbreviation:  ChemMedChem     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-25     Completed Date:  2012-08-22     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101259013     Medline TA:  ChemMedChem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  844-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Antimalarials / chemistry,  pharmacology
Cell Line, Tumor
High-Throughput Screening Assays / methods
Inhibitory Concentration 50
Liver / drug effects*,  parasitology
Malaria / drug therapy*
Models, Biological
Piperidines / chemistry,  pharmacology*
Plasmodium berghei*
Plasmodium falciparum*
Quinazolinones / chemistry,  pharmacology*
Sporozoites / physiology
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Antimalarials; 0/Piperidines; 0/Quinazolinones; L31MM1385E/halofuginone

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