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: 7849910
• 负责人: DAVID LEE WILLIAMS
• 金额: $ 18.75万
• 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/7849910
• 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（由申请人提供）：血吸虫病是一种重要的热带寄生虫性人类疾病。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，2000万人患有严重的疾病症状，28万人死于血吸虫病。随着药物的使用，传播率几乎没有变化，并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，因此迫切需要开发新的抗β-内酰胺酶体药物。在本申请中，我们建议将重点放在新的寄生虫酶，植物螯合素合酶，这是发现在寄生虫，但不是它的主机，作为一个目标，抗寄生虫药物的发展。植物螯合肽是由谷胱甘肽通过PCS合成的寡肽，在植物中作为螯合有毒重金属的主要手段而被充分表征。最近，PCS已被证明参与谷胱甘肽共轭异生物质的催化。这项R21探索性/开发性资助提案的目标是表征这种独特的、染色体特异性蛋白质作为药物靶点的潜力。我们的长期目标是确定寄生虫的途径，是不同的形式主机和利用这些差异作为合理的药物设计控制血吸虫病的目标。公共卫生相关性：血吸虫病是一种重要的被忽视的热带寄生虫病，影响到2.5亿多人，每年在70多个国家造成25万多人死亡。血吸虫病的治疗目前依赖于单一药物。该提案的目的是表征寄生虫中而非人类中独特发现的酶，以确定该酶是否将是开发用于血吸虫病治疗的新药的合适候选靶标，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。

项目成果

Characterization of the phytochelatin synthase from the human parasitic nematode Ancylostoma ceylanicum.

人类寄生线虫锡兰钩口线虫植物螯合素合酶的表征。

• DOI: 10.1016/j.molbiopara.2013.07.003
• 发表时间: 2013
• 期刊: Molecular and biochemical parasitology
• 影响因子: 1.5
• 作者: Rigouin,Coraline;Vermeire,JonJ;Nylin,Elyse;Williams,DavidL
• 通讯作者: Williams,DavidL

Towards an understanding of the function of the phytochelatin synthase of Schistosoma mansoni.

了解曼氏血吸虫植物螯合素合酶的功能。

• DOI: 10.1371/journal.pntd.0002037
• 发表时间: 2013
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Rigouin,Coraline;Nylin,Elyse;Cogswell,AlexisA;Schaumlöffel,Dirk;Dobritzsch,Dirk;Williams,DavidL
• 通讯作者: Williams,DavidL