The changing landscape of antiparasitic drug discovery for veterinary medicine

FMRFamide‐like peptides encoded on the flp‐18 precursor gene activate two isoforms of the orphan Caenorhabditis elegans G‐protein‐coupled receptor Y58G8A.4 heterologously expressed in mammalian cells

“…If that function is found essential for the maintenance of the parasite in the host, the receptor defined highthroughput screens could be established for finding nonpeptidic small molecules, either receptor agonists or antagonists, as potential antiparasitic drug candidates. [6][7][8][9] Despite intense efforts in many laboratories over the last decade, most of the C. elegans neuropeptide G-proteincoupled receptors (GPCRs) remain orphans, as only a few have been matched with their native ligands. [10][11][12][13][14][15][16] Functional expression of C. elegans neuropeptide GPCRs in mammalian expression systems has been challenging and problematic, mainly due to the apparently poor compatibility of mammalian G-proteins and other accessory proteins with heterelogously expressed nematode receptors.…”

Experimental infection of Haemonchus contortus strains resistant and susceptible to benzimidazoles and the effect on mast cells distribution in the stomach of Mongolian gerbils (Meriones unguiculatus)

“…An increasing number of worm populations resistant to the most common anthelmintics such as BZ carbamates has prompted the search of new classes of drugs by means of exploiting the worm's specific molecular mechanisms (Geary et al 2004). As yet, a new effective drug against intestinal nematodes such as H. contortus and T. colubriformis are not available, and therefore, a better understanding of the physiology of drug-resistant and drug-susceptible nematodes and their pathological effect on the host is necessary.…”

Parasitic nematodes—From genomes to control

“…It is intriguing that with each major drug class, despite distinct modes of action, resistant parasites have begun to appear within just a few years of commercial introduction (Kaplan, 2004). To bypass this, new molecular targets are being sought and tested, such as cysteine proteases (Selzer et al, 1999;Stepek et al, 2005) which seem to attack the parasite cuticle, parasite mitochondrial proteins involved in energy metabolism (Miyadera et al, 2003;Omura et al, 2001), neuropeptides and the nervous system (Geary et al, 2004;McVeigh et al, 2006;Mousley et al, 2005), phosphorylcholine metabolism that plays important roles in nematode development, fertility and survival (Lochnit et al, 2005;Palavalli et al, 2006), and other mechanism-based targets (Geary et al, 2004). Given the refocusing of the pharmaceutical research and development on drugs with known modes of action, targetbased anthelmintic discovery is likely to increasingly compete with more traditional in vivo screening of compound collections.…”