POTENTIAL TARGETS FOR NEW ANTISCHISTOSOMAL AGENTS

血吸虫病影响着全世界数亿人，每年造成数十万人死亡。这种内脏寄生虫病是由多种血吸虫属吸虫扁形虫引起的。抗血吸虫病的首选药物是吡喹酮，但最近开始出现对吡喹酮耐药的血吸虫种群的报告。新型驱虫药的合理设计有望开发出新的、高特异性的、有效的抗寄生虫药物。通过针对寄生虫特有的、对其生命周期至关重要的分子或分子部分靶向药物，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和被盖系统对其存在是绝对必要的，因此，这些系统功能的基础分子是新的驱虫剂的有吸引力的目标，包括在成虫被皮的宿主相互作用表面的情况下，新疫苗。然而，针对这些成分的药物设计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目标是电压依赖性钙（Ca2+）通道。Ca2+通道是可兴奋细胞的重要组成部分，参与了无数Ca2+依赖性过程的调节。我们克隆了两个与哺乳动物Ca2+通道a1亚基同源的mansoni cDNA片段。一个与哺乳动物的l型Ca2+通道序列最为相似；另一个与非l型通道最为相似。我们建议：1)克隆和测序这些通道亚型的全长cdna；2)研究这两个序列及其蛋白产物的表达模式；3)明确表达通道的生理和药理学；4)利用嵌合和突变的a1亚基，探索这些分子的结构/功能关系，以期找到新的有效抗血吸虫药物的靶点。

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.