Is phytochelatin synthase an essential enzyme and drug target for schistosomiasis

植物螯合素合酶是血吸虫病的必需酶和药物靶标吗

• 批准号: 7573526
• 负责人: DAVID LEE WILLIAMS
• 金额: $ 22.5万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7573526
• 关键词: Affect; Alternative Therapies; Animals; Antischistosomal Agents; Applications Grants; Biology; Catabolism; Cessation of life; Combined Modality Therapy; Country; Databases; Dependence; Development; Disease; Drug Delivery Systems; Drug Design; Drug resistance; Drug usage; Enzymes; Exploratory/Developmental Grant; Expressed Sequence Tags; Gene Expression; Gene Proteins; Genes; Genome; Glutathione; Glutathione Metabolism Pathway; Goals; Heavy Metals; Hemeproteins; Hemoglobin; Human; Individual; Iron; Lead; Life Cycle Stages; Measurable; Metabolism; Metalloproteins; Metals; Mitochondria; Monitor; Oligopeptides; Parasites; Parasitic Diseases; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plant Proteins; Plants; Play; Praziquantel; Process; Protein Databases; Proteins; RNA Interference; Recombinants; Schistosoma; Schistosoma mansoni; Schistosomiasis; Staging; Superoxide Dismutase; Symptoms; Testing; Xenobiotics; chelation; chemotherapy; cofactor; drug development; genome sequencing; human disease; neglect; novel; pathogen; phytochelatin; prevent; public health relevance; transmission process

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.

描述(申请人提供)：血吸虫病是一种重要的热带寄生虫病。虽然一种有效的抗血吸虫病药物正在使用中，但据估计，每年有2亿人感染，2000万人出现严重的疾病症状，28万人死于血吸虫病。传播率随着药物的使用几乎没有变化，而且有证据表明抗药性寄生虫的发展。由于目前没有合适的替代疗法可用，因此迫切需要开发新的抗血吸虫药物。在这项应用中，我们建议将重点放在新的寄生虫酶，植物螯合素合成酶，它在寄生虫中发现，但不是它的宿主，作为抗血吸虫药物开发的靶标。植物螯合素是一种由谷胱甘肽合成的寡肽，在植物中被认为是隔离有毒重金属的主要手段。最近，PCS被证明参与了谷胱甘肽结合的外源生物的分解代谢。这项R21探索性/发展资助提案的目标是描述这种独特的血吸虫特异性蛋白作为药物靶点的潜力。我们的长期目标是识别不同于宿主的寄生虫途径，并利用这些差异作为合理设计血吸虫病控制药物的靶点。公共卫生意义：血吸虫病是一种重要的被忽视的热带寄生虫病，影响着2.5亿多人，每年在70多个国家造成超过25万人死亡。目前，血吸虫病的治疗依赖于一种药物。这项提议的目标是确定一种在寄生虫中发现的独特的酶的特征，而不是在人类中发现的酶，以确定这种酶是否将成为开发血吸虫病治疗新药的合适候选靶点，用于预防耐药寄生虫的联合疗法或用于在寄生虫产生抗药性的情况下进行化疗。