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Infektiologie Update 2014: 24. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

16. - 18.10.2014, Weimar

Target-based discovery of novel inhibitors of enzymatic targets from Wolbachia endosymbionts and evaluation as antifilarial drug candidates

Meeting Abstract

  • Christian S. Lentz - Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany; Stanford University School of Medicine, Dept. of Pathology, Stanford, USA
  • Victoria S. Halls - LIMES Institute, Chemical Biology & Medicinal Chemistry Unit, Universität Bonn, Bonn, Germany
  • Jeffrey S. Hannam - LIMES Institute, Chemical Biology & Medicinal Chemistry Unit, Universität Bonn, Bonn, Germany
  • Achim Hoerauf - Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany
  • Michael Famulok - LIMES Institute, Chemical Biology & Medicinal Chemistry Unit, Universität Bonn, Bonn, Germany
  • Kennet M. Pfarr - Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany

Infektiologie Update 2014. 24. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG). Weimar, 16.-18.10.2014. Düsseldorf: German Medical Science GMS Publishing House; 2014. Doc14peg20

doi: 10.3205/14peg20, urn:nbn:de:0183-14peg200

Published: October 2, 2014

© 2014 Lentz et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

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

1.
Lentz CS, Halls V, Hannam JS, Niebel B, Struebing U, Mayer G, Hoerauf A, Famulok M, Pfarr KM. A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro. Chem Biol. 2013 Feb 21;20(2):177-87. DOI: 10.1016/j.chembiol.2012.11.009 External link
2.
Lentz CS, Halls VS, Hannam JS, Strassel S, Lawrence SH, Jaffe EK, Famulok M, Hoerauf A, Pfarr KM. wALADin Benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs. J Med Chem. 2014 Mar 27;57(6):2498-510. DOI: 10.1021/jm401785n External link
3.
Lentz CS, Stumpfe D, Bajorath J, Famulok M, Hoerauf A, Pfarr KM. New chemotypes for wALADin1-like inhibitors of delta-aminolevulinic acid dehydratase from Wolbachia endobacteria. Bioorg Med Chem Lett. 2013 Oct 15;23(20):5558-62. DOI: 10.1016/j.bmcl.2013.08.052 External link
4.
Lentz CS, Sattler J, Fendler M, Gottwald S, Halls VS, Strassel S, Arriens S, Hannam JS, Specht S, Famulok M, Mueller AK, Hoerauf A, Pfarr KM. In vitro activity of wALADin-benzimidazoles against different life-cycle stages of Plasmodium parasites. Antimicrob Agents Chemother. 2014 [manuscript accepted].