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  A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro

Lentz, C. S., Halls, V., Hannam, J. S., Niebel, B., Strübing, U., Mayer, G., et al. (2013). A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro. Chemistry & Biology, 20(2), 177-87. doi:10.1016/j.chembiol.2012.11.009.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63F6-0 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0028-63F7-E
Genre: Journal Article

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Lentz, C. S., Author
Halls, V., Author
Hannam, J. S., Author
Niebel, B., Author
Strübing, U., Author
Mayer, G., Author
Hoerauf, A., Author
Famulok, M.1, Author
Pfarr, K. M., Author
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1External Organizations, ou_persistent22              

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Free keywords: Animals Antiprotozoal Agents/chemistry/*pharmacology/therapeutic use Benzimidazoles/chemistry/*pharmacology/therapeutic use Drug Design Elephantiasis, Filarial/drug therapy Filarioidea/*drug effects Heme/*biosynthesis High-Throughput Screening Assays Humans Kinetics Magnesium/chemistry/metabolism Porphobilinogen Synthase/antagonists & inhibitors/metabolism Symbiosis Thiophenes/chemistry/*pharmacology/therapeutic use Wolbachia/enzymology/*metabolism
 Abstract: Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic alpha-proteobacteria Wolbachia are essential for these parasites throughout their life cycle. Using a high-throughput chemical screen, we identified a benzimidazole compound, wALADin1, that selectively targets the delta-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes with the Mg(2+)-induced activation of wALAD. This mechanism inherently excludes activity against the Zn(2+)-dependent human ortholog and might be translatable to Mg(2+)-responsive orthologs of other bacterial or protozoan pathogens. The specificity profile of wALADin1 derivatives reveals chemical features responsible for inhibitory potency and species selectivity. Our findings validate wALADins as a basis for developing potent leads that meet current requirements for antifilarial drugs.

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 Dates: 2013
 Publication Status: Issued
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 Identifiers: Other: 23438747
DOI: 10.1016/j.chembiol.2012.11.009
ISSN: 1879-1301 (Electronic)
ISSN: 1074-5521 (Linking)
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Title: Chemistry & Biology
  Alternative Title : Chem. Biol.
Source Genre: Journal
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Pages: - Volume / Issue: 20 (2) Sequence Number: - Start / End Page: 177 - 87 Identifier: -