Artikel
Target-based discovery of novel inhibitors of enzymatic targets from Wolbachia endosymbionts and evaluation as antifilarial drug candidates
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Veröffentlicht: | 2. Oktober 2014 |
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Gliederung
Text
Lymphatic Filariasis and Onchocerciasis are neglected tropical diseases caused by parasitic filarial nematodes affecting more than 150 million people worldwide. The final success of mass drug administration programs (MDA) in endemic countries using combination therapies of diethycarbamazine or ivermectin with albendazole mainly targeting transmission stages of the parasite is threatened by the emergence of suboptimal drug responses and the lack of efficacy against adult worms that persist in the human host for years. Depletion of the worms’ endosymbiotic α-proteobacteria Wolbachia by doxycycline represents an efficient alternative therapeutic strategy inducing long-term sterility and death of adult worms. While the long treatment regimen and contraindications for certain population groups make the implementation of doxycycline in MDA difficult, exploiting drug targets within the endobacteria is a promising strategy for the development of new antifilarial drug leads.
Wolbachia have conserved a functional de novo heme biosynthesis pathway and are expected to provide their filarial hosts, which are unable to synthesize tetrapyrroles de novo, with these essential biomolecules. Inhibition of this metabolic pathway with a subsequent loss of heme-dependent enzyme function in both endosymbiont and filarial host is presumed to be lethal for the parasite. In this work a chemical library of ~18,000 drug-like small molecules was screened for inhibitors of the recombinant heme biosynthesis enzyme δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia of the filarial nematode Brugia malayi. This has led to the identification of the trisubstituted benzimidazole inhibitor “Wolbachia ALAD inhibitor 1” (wALADin1, IC50 ~22 µM) which had no effect on the human ALAD ortholog [1]. The selectivity was explained by the molecular mode of action of wALADin1, i.e. interference with an allosteric activation mechanism present in Wolbachia ALAD (wALAD) as well as various orthologs from human pathogens and other organisms, but not in the human enzyme [2]. The specific antifilarial activity of wALADin1 was demonstrated on adult female worms ex vivo, where the compound induced a characteristic low-motility phenotype with reduced viability in Wolbachia-containing rodent filarial nematodes, but not in Wolbachia-free filariae [1].
Along with the characterization of the molecular mode of inhibition [1], [2] and the identification of a specific wALAD inhibitor based on an alternative non-benzimidazole chemotype (wALADin2) [3], systematic Structure-Activity-Relationship studies on wALADin1-benzimidazole derivatives performed on wALAD [1] and a representative series of ALAD orthologs from other organisms [2] provide the framework for the future development of more potent wALAD inhibitors with potential antiflilarial activity in vivo. Beyond the field of filarial research, our results indicate that wALADin-like benzimidazoles may also gain importance as herbicidal, antimicrobial [2] or antimalarial agents [4].
References
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