A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
Identifieur interne : 003931 ( Main/Exploration ); 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
Affiliations:
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Lentz</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Halls, Victoria" sort="Halls, Victoria" uniqKey="Halls V" first="Victoria" last="Halls">Victoria Halls</name></author><author><name sortKey="Hannam, Jeffrey S" sort="Hannam, Jeffrey S" uniqKey="Hannam J" first="Jeffrey S" last="Hannam">Jeffrey S. 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débit</term><term>Thiophènes</term></keywords></textClass></profileDesc></teiHeader><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></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>District de Cologne</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li></settlement></list><tree><noCountry><name sortKey="Famulok, Michael" sort="Famulok, Michael" uniqKey="Famulok M" first="Michael" last="Famulok">Michael Famulok</name><name sortKey="Halls, Victoria" sort="Halls, Victoria" uniqKey="Halls V" first="Victoria" last="Halls">Victoria Halls</name><name sortKey="Hannam, Jeffrey S" sort="Hannam, Jeffrey S" uniqKey="Hannam J" first="Jeffrey S" last="Hannam">Jeffrey S. Hannam</name><name sortKey="Hoerauf, Achim" sort="Hoerauf, Achim" uniqKey="Hoerauf A" first="Achim" last="Hoerauf">Achim Hoerauf</name><name sortKey="Mayer, Gunter" sort="Mayer, Gunter" uniqKey="Mayer G" first="Günter" last="Mayer">Günter Mayer</name><name sortKey="Niebel, Bjorn" sort="Niebel, Bjorn" uniqKey="Niebel B" first="Björn" last="Niebel">Björn Niebel</name><name sortKey="Pfarr, Kenneth M" sort="Pfarr, Kenneth M" uniqKey="Pfarr K" first="Kenneth M" last="Pfarr">Kenneth M. Pfarr</name><name sortKey="Strubing, Uta" sort="Strubing, Uta" uniqKey="Strubing U" first="Uta" last="Strübing">Uta Strübing</name></noCountry><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Lentz, Christian S" sort="Lentz, Christian S" uniqKey="Lentz C" first="Christian S" last="Lentz">Christian S. Lentz</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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