edocDrug targets of the heartworm, "Dirofilaria immitis"ChristelleGodelauthorThe filarial parasite, Dirofilaria immitis, infects dogs and canids in warm and tropical areas of the globe. Located in the right pulmonary arteries, the heartworm infection is a severe and potentially fatal disease; caused mainly by the adult worm stages. The zoonotic roundworm is transmitted by various mosquitoes, Culicidae. Currently, control measures are based on monthly prophylaxis with macrocyclic lactones (MLs). The only adulticide treatment is melarsomine dihydrochloride injected intramuscularly which can cause complications. Resistance is emerging against the MLs, increasing the necessity to find novel anthelmintics. The recently discovered class of anthelmintics, amino acetonitriles derivatives (AADs), with a new mode of action brought hope in the battle against helminth parasites. The aim of this thesis was to find candidate targets of AADs and other potential anthelmintics in D. immitis genome that could be used as therapeutic targets. The first chapter discusses the possible mechanisms of antiparasitic drug action and selectivity. The second chapter tests and confirms the efficacy of AADs against D. immitis in vitro. This suggests the presence of receptor(s) to AADs in the heartworm, a hypothesis which can be tested by genome sequencing. The third chapter narrates the story of the genome project of the heartworm; de novo sequenced with Illumina HiSeq and assembled with Abyss and Velvet. This did not indicate that there is an AAD receptor (DEG-3-subfamily), to Caenorhabditis elegans and Haemonchus contortus in D. immitis genome. In fact, D. immitis does not appear to possess a single gene of the DEG-3 subfamily of acetylcholine receptors, the targets of monepantel. However, in-depth studies of the genome through exclusion criteria established a list of novel potential drug targets. The fourth chapter further investigates the presumed loss of the DEG-3-subfamily in D. immitis and relates this finding to the sensitivity against both monepantel enantiomers in vitro and in vivo. The fifth chapter picks up some of the newly identified candidate drug targets. It tests the predicted targets against the heartworm with known inhibitors. This thesis presents a genomic approach to identify potential targets and new anthelmintics. I hope that, the genomic approach will support the development of drugs against the heartworm and related parasites. 2012University_of_Basel;Faculty_of_ScienceThesis

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