Benelux Congress of Zoology edition:13 location:Leuven date:27-28 october 2006
Parasitic nematodes cause a great disease problem in humans and in grazing livestock systems worldwide. Control of the diseases they cause relies on drug treatments that are threatened by the development of resistance. New validated drug targets are required to allow development of new classes of anthelmintic drugs. G protein-coupled receptors (GPCRs), which play an important role in signal transduction, are an excellent class of drug targets. First we select a number of GPCRs in the C. elegans genome with a relevant RNAi phenotype (lethal, sterile,…). Since its genome sequence became available in 1998, large-scale RNAi screens have greatly accelerated elucidation of gene functions in C. elegans. Most of these predicted GPCRs are still orphan receptors. We deorphanize GPCRs, predicted to bind peptides, using a reverse pharmacology strategy. The expressed orphan receptor is used as a hook to identify the corresponding synthetic and/or natural ligand(s). This strategy has already proven its value in the deorphanization of 3 neuropeptide GPCRs in our lab. Peptides itself are not stable in a worm’s body when applied as a drug, so we use peptidomimetics. These molecules should bind the receptor but not transduce its signal. This results in a loss of function of the receptor which is the same as the RNAi phenotype on which the selection of the orphan receptor was based. In this way we can validate GPCRs as targets for a new class of anthelmintics.