Article
Nature 452, 176-180 (13 March 2008) | doi:10.1038/nature06722; Received 8 June 2007; Accepted 15 January 2008
A new class of anthelmintics effective against drug-resistant nematodes
Ronald Kaminsky1, Pierre Ducray2, Martin Jung1, Ralph Clover3, Lucien Rufener1,4, Jacques Bouvier1, Sandra Schorderet Weber1, Andre Wenger1, Susanne Wieland-Berghausen2, Thomas Goebel2, Noelle Gauvry2, François Pautrat2, Thomas Skripsky2, Olivier Froelich1, Clarisse Komoin-Oka5, Bethany Westlund3, Ann Sluder3 & Pascal Mäser4
- Novartis Centre de Recherche Santé Animale, CH-1566 St Aubin (FR), Switzerland
- Novartis Animal Health Inc., CH-4002 Basel, Switzerland
- Cambria Biosciences, Woburn, Massachusetts 01801, USA
- Institute of Cell Biology, University of Bern, CH-3012 Bern, Switzerland
- Laboratoire Central Vétérinaire de Bingerville, BP 206, Lanada, Côte d'Ivoire
Correspondence to: Ronald Kaminsky1 Correspondence and requests for materials should be addressed to R.K. (Email: ronald.kaminsky@novartis.com).
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.