POTENTIAL TARGETS FOR NEW ANTISCHISTOSOMAL AGENTS

血吸虫病影响着全世界数亿人，每年导致数十万人死亡。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，但最近开始出现对吡喹酮耐药的血吸虫种群的报道。新型驱虫剂的合理设计有望开发出高度特异、有效的新型抗寄生虫药物。通过针对寄生虫特有的、对实现其生命周期至关重要的分子或分子部分进行靶向治疗，有可能开发出一系列非常有效、但对宿主几乎没有副作用的治疗方法。寄生扁虫的神经肌肉和被盖系统对其生存是绝对必要的，因此这些系统功能的潜在分子是新驱虫剂的诱人靶标，包括成虫被层与宿主相互作用的表面，新的疫苗。然而，针对这些成分的药物的设计需要有关相关分子或途径的广泛分子数据。一个特别吸引人的靶点是电压依赖的钙(钙)通道。钙通道是可兴奋细胞的重要组成部分，参与了无数钙依赖过程的调节。我们从曼氏血吸虫中克隆了两个与哺乳动物钙通道A1亚基同源的基因片段。一个与哺乳动物L型钙通道序列最相似，另一个与非L型钙通道序列最相似。我们建议：1)克隆和测序这些通道亚型的全长cDNA；2)检测两个序列及其蛋白产物的表达模式；3)确定表达通道的生理和药理学；4)利用嵌合和突变的A1亚基来探索这些分子的结构/功能关系，所有这些都是为了识别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.