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（申请人提供）：血吸虫病是一种重要的人类热带寄生虫病。尽管有效的抗血吸虫药物正在使用，但估计每年仍有 2 亿人受到感染，2000 万人出现严重疾病症状，28 万人死于血吸虫病。使用该药物后，传播率几乎没有变化，并且有证据表明出现了耐药寄生虫。由于目前没有合适的替代疗法，因此迫切需要开发新型抗血吸虫药物。在本申请中，我们建议重点关注新型寄生虫酶——植物螯合素合酶，该酶存在于寄生虫而非其宿主中，可作为抗血吸虫药物开发的靶点。植物螯合素是通过 PCS 从谷胱甘肽合成的寡肽，在植物中作为隔离有毒重金属的主要手段已得到充分表征。最近，PCS 已被证明参与谷胱甘肽缀合的异生物质的分解代谢。该 R21 探索性/开发资助提案的目标是表征这种独特的血吸虫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与宿主不同的寄生虫途径，并利用这些差异作为控制血吸虫病的合理药物设计的目标。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，影响超过 2.5 亿人，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单一药物。该提案的目标是表征一种在寄生虫中而不是在人类中独特存在的酶，以确定这种酶是否是开发血吸虫病治疗新药的合适候选靶点，用于联合疗法以防止耐药寄生虫的出现，或在寄生虫产生耐药性时用于化疗。

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