A new class of anthelmintics effective against drug-resistant nematodes (original) (raw)

Nature volume 452, pages 176–180 (2008)Cite this article

Abstract

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics—the benzimidazoles, imidazothiazoles and macrocyclic lactones—has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.

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Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Hcdes-2H sequences have been deposited in GenBank under accession numbers EF659746, EF659747, EF659748, EF659749, EF659750, EF659751, EF659752, EF659753, EF659754, EF659755, EF659756, EF659757, EF659758, EF659759, EF659760.

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Acknowledgements

We thank F. Schroeder, E. Pradervand, S. Mulhauser, J. Lambert, D. Mosimann and A. Kazimi for technical assistance; C. Johnson for providing an ivermectin-resistant C. elegans strain; and C. Kempter for support on chemical characterization of AADs. We also thank S. Nanchen, B. Hosking, A. Redpath and R. Steiger for thorough review of and comments on the manuscript. P.M. is supported by the Swiss National Science Foundation.

Author information

Authors and Affiliations

  1. Novartis Centre de Recherche Santé Animale, CH-1566 St Aubin (FR), Switzerland
    Ronald Kaminsky, Martin Jung, Lucien Rufener, Jacques Bouvier, Sandra Schorderet Weber, Andre Wenger & Olivier Froelich
  2. Novartis Animal Health Inc., CH-4002 Basel, Switzerland
    Pierre Ducray, Susanne Wieland-Berghausen, Thomas Goebel, Noelle Gauvry, François Pautrat & Thomas Skripsky
  3. Cambria Biosciences, Woburn, Massachusetts 01801, USA,
    Ralph Clover, Bethany Westlund & Ann Sluder
  4. Institute of Cell Biology, University of Bern, CH-3012 Bern, Switzerland
    Lucien Rufener & Pascal Mäser
  5. Laboratoire Central Vétérinaire de Bingerville, BP 206, Lanada, Côte d’Ivoire,
    Clarisse Komoin-Oka

Authors

  1. Ronald Kaminsky
  2. Pierre Ducray
  3. Martin Jung
  4. Ralph Clover
  5. Lucien Rufener
  6. Jacques Bouvier
  7. Sandra Schorderet Weber
  8. Andre Wenger
  9. Susanne Wieland-Berghausen
  10. Thomas Goebel
  11. Noelle Gauvry
  12. François Pautrat
  13. Thomas Skripsky
  14. Olivier Froelich
  15. Clarisse Komoin-Oka
  16. Bethany Westlund
  17. Ann Sluder
  18. Pascal Mäser

Corresponding author

Correspondence toRonald Kaminsky.

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Competing interests

The value of patent WO2002049641 may be affected by publication of the article. Concerning pending patent applications, the authors declare that they are bound by confidentiality agreements that prevent them from disclosing their financial interest in this work.

Supplementary information

Supplementary Information

The file contains Supplementary Methods with details on the chemical synthesis of amino-acetonitrile derivatives (AADs); Supplementary Data with chiral resolution of AAD-1470 and biological activity of the enantiomers; Supplementary Figures S1-S2 illustrating NMR spectra of AADs (Figure S1) and multiple alignment of nicotinic acetylcholine receptor alpha-subunits (Figure S2); and Supplementary Tables S1-S3 with pharmacological (Tables S1 and S3) and genetic (Table S2) data of Caenorhabditis elegans mutants. (PDF 698 kb)

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Kaminsky, R., Ducray, P., Jung, M. et al. A new class of anthelmintics effective against drug-resistant nematodes.Nature 452, 176–180 (2008). https://doi.org/10.1038/nature06722

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Editorial Summary

A new class of anthelmintic

The use of drugs to control pathogenic roundworms in farm animals, an important tool of modern livestock management, is being undermined by the spread of multidrug resistance against all three types of anthelmintic currently available. No new anthelmintic class has reached the market in the past 25 years save the cyclodepsipeptides, indicated for use in cats but not in livestock. Kaminsky et al. now report the discovery of a new class of anthelmintics — amino-acetonitrile derivatives — that appear to act via acetylcholine receptors specific to nematodes. They are effective against various livestock pathogens, and if successful in animals, may also provide alternative drugs for use in humans, where drug resistance is also increasing.

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