Is phytochelatin synthase an essential enzyme and drug target for schistosomiasis

描述（申请人提供）：血吸虫病是一种重要的热带人类寄生虫病。虽然使用了一种有效的抗血吸虫药物，但据估计，每年有2亿人感染，2 000万人患有严重的疾病症状，28万人死于血吸虫病。由于使用该药物，传播率几乎没有变化，而且有证据表明出现了耐药寄生虫。由于目前还没有合适的替代疗法，因此迫切需要开发新的抗血吸虫药。在这个应用中，我们建议把重点放在新的寄生虫酶，植物螯合素合成酶，发现在寄生虫，而不是其宿主，作为抗血吸虫药物开发的靶点。植物螯合素是一种由谷胱甘肽经PCS合成的寡肽，在植物中作为隔离有毒重金属的主要手段已被广泛研究。最近，PCS已被证明参与谷胱甘肽结合的异种抗生素的分解代谢。这项R21探索性/发展性拨款提案的目标是表征这种独特的血吸虫特异性蛋白作为药物靶点的潜力。我们的长期目标是确定与宿主不同的寄生虫途径，并利用这些差异作为合理的药物设计靶点来控制血吸虫病。公共卫生相关性：血吸虫病是一种被忽视的重要热带寄生虫病，每年在70多个国家影响2.5亿多人，造成25万多人死亡。目前血吸虫病的治疗依赖于一种药物。本提案的目标是表征一种仅在寄生虫中发现而非在人类中发现的酶，以确定该酶是否将成为开发血吸虫病治疗新药的合适候选靶点，用于联合治疗以防止耐药寄生虫的出现，或用于寄生虫产生耐药性的化疗。

DESCRIPTION (provided by applicant): Schistosomiasis is an important tropical parasitic human disease. Although an effective anti-schistosome drug is in use, it is estimated that 200 million people are infected, 20 million individuals suffer severe disease symptoms, and 280,000 people die annually from schistosomiasis. Transmission rates have changed little with the use of the drug and there is evidence for the development of drug resistant parasites. Because there is currently no suitable alternative therapy available there is an urgent need for the development of novel antischistosomal agents. In this application we propose to focus on novel parasite enzyme, phytochelatin synthase, which is found in the parasite, but not its host, as a target for antischistosomal drug development. Phytochelatins, which have been well characterized in plants where they serve as the primary means of sequestering toxic heavy metals, are oligopeptides synthesized from glutathione by PCS. More recently, PCS have been shown to be involved in the catabolism of glutathione-conjugated xenobiotics. The goal of this R21 exploratory/developmental grant proposal is to characterize the potential as a drug target of this unique, schistosome-specific protein. Our long-term goals are to identify parasite pathways that are different form host and to exploit these differences as targets for rational drug design for schistosomiasis control. PUBLIC HEALTH RELEVANCE: Schistosomiasis is an important neglected tropical parasitic disease affecting more than 250 million people and causing more than a quarter of a million deaths annually in over 70 countries. Treatment for schistosomiasis currently relies on a single drug. The goal of this proposal is to characterize an enzyme found uniquely in the parasite and not in humans to determine if this enzyme will be a suitable candidate target to develop new drugs for schistosomiasis treatment to be used in combination therapies to prevent the emergence of drug resistant parasites or for chemotherapy should parasites develop drug resistance.