POTENTIAL TARGETS FOR NEW ANTISCHISTOSOMAL AGENTS

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Schistosomiasis affects hundreds of millions of people worldwide, and kills hundreds of thousands each year. This visceral parasitic disease is caused by a variety of trematode flatworms of the genus Schistosoma. The drug of choice against schistosomiasis is praziquantel, but reports of schistosome populations with praziquantel resistance have recently begun to appear. The rational design of novel anthelmintic agents holds the promise of new, highly specific and effective, antiparasitical drugs. By targeting agents against molecules, or portions of molecules, specific to the parasite and crucial for realization of its life cycle, it may be possible to develop a battery of treatments that are very potent, but have few side effects for the host. The neuromuscular and tegumental systems of a parasitic flatworm are absolutely essential for its existence, and the molecules underlying the functioning of these systems are thus attractive targets for new anthelmintic agents, including, in the case of the host-interactive surface of the adult worm's tegument, new vaccines. However, the design of agents that target these components requires extensive molecular data about relevant molecules or pathways. One particularly attractive target is the voltage-dependent calcium (Ca2+) channel. Ca2+ channels are crucial components of excitable cells and participate in the regulation of innumerable Ca2+-dependent processes. We have cloned two cDNA fragments from S. mansoni which are homologous to the a1 subunit of mammalian Ca2+ channels. One is most similar to mammalian L-type Ca2+ channel sequences; the other most closely resembles non L-type channels. We propose to: 1) clone and sequence the full-length cDNAs for these channel subtypes; 2) examine the patterns of expression for the two sequences and their protein products; 3) define the physiology and pharmacology of the expressed channels; and 4) explore the structure/function relations of these molecules by using chimeric and mutated a1 subunits, all towards the goal of identifying target sites for new and effective antischistosomal agents.