A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
Identifieur interne : 003931 ( Main/Curation ); précédent : 003930; suivant : 003932A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
Auteurs : Christian S. Lentz [Allemagne] ; Victoria Halls ; Jeffrey S. Hannam ; Björn Niebel ; Uta Strübing ; Günter Mayer ; Achim Hoerauf ; Michael Famulok ; Kenneth M. PfarrSource :
- Chemistry & biology [ 1879-1301 ] ; 2013.
Descripteurs français
- KwdFr :
- Animaux, Antiprotozoaires (), Antiprotozoaires (pharmacologie), Antiprotozoaires (usage thérapeutique), Benzimidazoles (), Benzimidazoles (pharmacologie), Benzimidazoles (usage thérapeutique), Cinétique, Conception de médicament, Filarioidea (), Filariose lymphatique (traitement médicamenteux), Humains, Hème (biosynthèse), Magnésium (), Magnésium (métabolisme), Porphobilinogene synthase (antagonistes et inhibiteurs), Porphobilinogene synthase (métabolisme), Symbiose, Tests de criblage à haut débit, Thiophènes (), Thiophènes (pharmacologie), Thiophènes (usage thérapeutique), Wolbachia (enzymologie), Wolbachia (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Porphobilinogene synthase.
- biosynthèse : Hème.
- enzymologie : Wolbachia.
- métabolisme : Magnésium, Porphobilinogene synthase, Wolbachia.
- pharmacologie : Antiprotozoaires, Benzimidazoles, Thiophènes.
- traitement médicamenteux : Filariose lymphatique.
- usage thérapeutique : Antiprotozoaires, Benzimidazoles, Thiophènes.
- Animaux, Antiprotozoaires, Benzimidazoles, Cinétique, Conception de médicament, Filarioidea, Humains, Magnésium, Symbiose, Tests de criblage à haut débit, Thiophènes.
English descriptors
- KwdEn :
- Animals, Antiprotozoal Agents (chemistry), Antiprotozoal Agents (pharmacology), Antiprotozoal Agents (therapeutic use), Benzimidazoles (chemistry), Benzimidazoles (pharmacology), Benzimidazoles (therapeutic use), Drug Design, Elephantiasis, Filarial (drug therapy), Filarioidea (drug effects), Heme (biosynthesis), High-Throughput Screening Assays, Humans, Kinetics, Magnesium (chemistry), Magnesium (metabolism), Porphobilinogen Synthase (antagonists & inhibitors), Porphobilinogen Synthase (metabolism), Symbiosis, Thiophenes (chemistry), Thiophenes (pharmacology), Thiophenes (therapeutic use), Wolbachia (enzymology), Wolbachia (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Porphobilinogen Synthase.
- chemical , biosynthesis : Heme.
- chemical , chemistry : Antiprotozoal Agents, Benzimidazoles, Magnesium, Thiophenes.
- chemical , metabolism : Magnesium, Porphobilinogen Synthase.
- chemical , pharmacology : Antiprotozoal Agents, Benzimidazoles, Thiophenes.
- chemical , therapeutic use : Antiprotozoal Agents, Benzimidazoles, Thiophenes.
- drug effects : Filarioidea.
- drug therapy : Elephantiasis, Filarial.
- enzymology : Wolbachia.
- metabolism : Wolbachia.
- Animals, Drug Design, High-Throughput Screening Assays, Humans, Kinetics, Symbiosis.
Abstract
Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-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 δ-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.
DOI: 10.1016/j.chembiol.2012.11.009
PubMed: 23438747
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pubmed:23438747Le document en format XML
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<term>Antiprotozoal Agents (chemistry)</term>
<term>Antiprotozoal Agents (pharmacology)</term>
<term>Antiprotozoal Agents (therapeutic use)</term>
<term>Benzimidazoles (chemistry)</term>
<term>Benzimidazoles (pharmacology)</term>
<term>Benzimidazoles (therapeutic use)</term>
<term>Drug Design</term>
<term>Elephantiasis, Filarial (drug therapy)</term>
<term>Filarioidea (drug effects)</term>
<term>Heme (biosynthesis)</term>
<term>High-Throughput Screening Assays</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Magnesium (chemistry)</term>
<term>Magnesium (metabolism)</term>
<term>Porphobilinogen Synthase (antagonists & inhibitors)</term>
<term>Porphobilinogen Synthase (metabolism)</term>
<term>Symbiosis</term>
<term>Thiophenes (chemistry)</term>
<term>Thiophenes (pharmacology)</term>
<term>Thiophenes (therapeutic use)</term>
<term>Wolbachia (enzymology)</term>
<term>Wolbachia (metabolism)</term>
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<term>Antiprotozoaires (pharmacologie)</term>
<term>Antiprotozoaires (usage thérapeutique)</term>
<term>Benzimidazoles ()</term>
<term>Benzimidazoles (pharmacologie)</term>
<term>Benzimidazoles (usage thérapeutique)</term>
<term>Cinétique</term>
<term>Conception de médicament</term>
<term>Filarioidea ()</term>
<term>Filariose lymphatique (traitement médicamenteux)</term>
<term>Humains</term>
<term>Hème (biosynthèse)</term>
<term>Magnésium ()</term>
<term>Magnésium (métabolisme)</term>
<term>Porphobilinogene synthase (antagonistes et inhibiteurs)</term>
<term>Porphobilinogene synthase (métabolisme)</term>
<term>Symbiose</term>
<term>Tests de criblage à haut débit</term>
<term>Thiophènes ()</term>
<term>Thiophènes (pharmacologie)</term>
<term>Thiophènes (usage thérapeutique)</term>
<term>Wolbachia (enzymologie)</term>
<term>Wolbachia (métabolisme)</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiprotozoal Agents</term>
<term>Benzimidazoles</term>
<term>Magnesium</term>
<term>Thiophenes</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Magnesium</term>
<term>Porphobilinogen Synthase</term>
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<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiprotozoal Agents</term>
<term>Benzimidazoles</term>
<term>Thiophenes</term>
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<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiprotozoal Agents</term>
<term>Benzimidazoles</term>
<term>Thiophenes</term>
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<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Porphobilinogene synthase</term>
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<keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Hème</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Filarioidea</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Elephantiasis, Filarial</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Wolbachia</term>
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<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Wolbachia</term>
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<term>Porphobilinogene synthase</term>
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<term>Benzimidazoles</term>
<term>Thiophènes</term>
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<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antiprotozoaires</term>
<term>Benzimidazoles</term>
<term>Thiophènes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Drug Design</term>
<term>High-Throughput Screening Assays</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Symbiosis</term>
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<term>Antiprotozoaires</term>
<term>Benzimidazoles</term>
<term>Cinétique</term>
<term>Conception de médicament</term>
<term>Filarioidea</term>
<term>Humains</term>
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<front><div type="abstract" xml:lang="en">Lymphatic filariasis and onchocerciasis are severe diseases caused by filarial worms and affect more than 150 million people worldwide. Endosymbiotic α-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 δ-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.</div>
</front>
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