A new class of anthelmintics effective against drug-resistant nematodes

Nature. 2008 Mar 13;452(7184):176-80. doi: 10.1038/nature06722.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Amino Acid Sequence
  • Aminoacetonitrile / adverse effects
  • Aminoacetonitrile / analogs & derivatives*
  • Aminoacetonitrile / pharmacokinetics
  • Aminoacetonitrile / pharmacology*
  • Animals
  • Anthelmintics / chemistry
  • Anthelmintics / classification*
  • Anthelmintics / pharmacokinetics
  • Anthelmintics / pharmacology*
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cattle
  • Cattle Diseases / drug therapy
  • Cattle Diseases / parasitology
  • Drug Resistance* / genetics
  • Larva / drug effects
  • Larva / genetics
  • Molecular Sequence Data
  • Nematoda / drug effects*
  • Nematoda / genetics
  • Nematoda / physiology
  • Parasitic Diseases, Animal / drug therapy
  • Parasitic Diseases, Animal / parasitology*
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Sheep / parasitology
  • Sheep Diseases / drug therapy
  • Sheep Diseases / parasitology

Substances

  • ACR-23 protein, C elegans
  • Anthelmintics
  • Caenorhabditis elegans Proteins
  • Receptors, Nicotinic
  • Aminoacetonitrile

Associated data

  • GENBANK/EF659746
  • GENBANK/EF659747
  • GENBANK/EF659748
  • GENBANK/EF659749
  • GENBANK/EF659750
  • GENBANK/EF659751
  • GENBANK/EF659752
  • GENBANK/EF659753
  • GENBANK/EF659754
  • GENBANK/EF659755
  • GENBANK/EF659756
  • GENBANK/EF659757
  • GENBANK/EF659758
  • GENBANK/EF659759
  • GENBANK/EF659760