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

基本信息

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
项目类别：
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

项目摘要

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疾病。尽管正在使用一种有效的抗速剂药物，但据估计，有2亿人感染，2000万人患有严重的疾病症状，每年有280,000人死于血吸虫病。使用药物的传播率很少发生变化，并且有证据表明耐药寄生虫的发展。由于目前尚无合适的替代疗法，因此迫切需要开发新型的反chistosomal剂。在此应用中，我们建议将重点放在新型的寄生虫酶，植物胆素合酶中，该酶在寄生虫中发现，但不是其宿主，是抗毒体药物开发的靶标。植物胆素在它们是隔离有毒重金属的主要手段的植物中的特征是，是由PCS从谷胱甘肽合成的寡肽。最近，PC已被证明与谷胱甘肽偶联异生元的分解代谢有关。该R21探索性/发展赠款提案的目的是将潜力描述为这种独特的，具棘齿状特异性蛋白的药物靶标。我们的长期目标是确定不同形式的寄生虫途径，并利用这些差异作为血吸虫病控制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疾病，影响了2.5亿多人，并在70多个国家 /地区每年造成超过四分之一的死亡。目前，血吸虫病治疗依赖于一种药物。该提案的目的是表征在寄生虫中独特发现的酶，而不是在人类中确定该酶是否是开发新药物的候选靶标，用于开发新药物治疗，用于用于防止抗药性寄生虫或化学疗法的结合疗法中使用，或者应培养化学疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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。