POTENTIAL TARGETS FOR NEW ANTISCHISTOSOMAL AGENTS

血吸虫病影响全世界数亿人，每年造成数十万人死亡。 这种内脏寄生虫病是由血吸虫属的各种吸虫扁虫引起的。 治疗血吸虫病的首选药物是吡喹酮，但最近开始出现一些人群对吡喹酮产生耐药性的报道。 新型驱虫剂的合理设计有望成为新型、高度特异性和有效的抗寄生虫药物。 通过针对寄生虫特有的分子或分子的一部分的靶向药物，并对其生命周期的实现至关重要，有可能开发出一系列非常有效的治疗方法，但对宿主几乎没有副作用。寄生扁形虫的神经肌肉系统和体表系统对其存在是绝对必要的，因此，这些系统的功能的分子是新的驱虫剂的有吸引力的目标，包括在成虫的表皮的宿主相互作用表面的情况下，新的疫苗。 然而，设计靶向这些成分的药物需要有关相关分子或途径的大量分子数据。 一个特别有吸引力的靶点是电压依赖性钙（Ca2+）通道。 Ca2+通道是可兴奋细胞的重要组成部分，参与调节无数的Ca2+依赖性过程。 我们克隆了两个来自S. mansoni，其与哺乳动物Ca 2+通道的α 1亚基同源。 一个是最相似的哺乳动物L-型钙离子通道序列;其他最接近的非L-型通道。我们建议：1）克隆并测序这些通道亚型的全长cDNA; 2）检查这两个序列及其蛋白产物的表达模式; 3）定义表达通道的生理学和药理学;和4）通过使用嵌合和突变的a1亚基来探索这些分子的结构/功能关系，所有这些都是为了确定新的有效抗血吸虫药物的靶位点。

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.