Investigation of Giardiasis Using Click Chemistry Techniques

使用点击化学技术研究贾第鞭毛虫病

• 批准号: 7880926
• 负责人: Keith Allen Korthals
• 金额: $ 5.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880926
• 关键词: 4-nitroimidazole; Abdominal Pain; Adverse effects; Alkynes; Amino Acids; Azides; Binding; Biochemical; Biological Assay; Bioterrorism; Categories; Cells; Chemical Structure; Chemicals; Chemistry; Clinical; Cyst; Development; Diarrhea; Disease; Dose; Drug resistance; Effectiveness; Environment; Gel; Giardia; Giardia lamblia; Giardiasis; Goals; Human; Imagery; Immunoblotting; Incubated; Intestines; Investigation; Laboratories; Lead; Libraries; Mass Spectrum Analysis; Methods; Metronidazole; Metronidazole resistance; Microscopic; Modification; Nausea; Nitroimidazoles; Parasites; Peroxidases; Pharmaceutical Preparations; Process; Proteins; Proteomics; Reporting; Resistance; Screening procedure; Sewage; Streptavidin; Structure; Symptoms; Techniques; Time; United States; Water; adduct; base; chlorination; combat; cycloaddition; drinking water; gel electrophoresis; improved; pathogen; protein complex; treatment strategy; wasting; water treatment; waterborne

DESCRIPTION (provided by applicant): Giardiasis is an important cause of waterborne illness resulting from a one-celled microscopic parasite, Giardia intestinalis (also known as Giardia lamblia). The pathogenic cyst form is protected by an outer shell and can survive outside the body in the environment for long periods of time. It is resistant to water treatment processes such as ozonolysis and chlorination. Giardiasis is recognized as one of the most prevalent causes of waterborne illness originating from both drinking water and recreational water activities. Giardia is found throughout the world and in every region of the United States. Furthermore, G. lamblia is a credible bioterrorism threat because it is easily obtained, has a very low infectious dose, and causes severe symptoms such as abdominal pain, diarrhea, and nausea. Metronidazole is the current first line treatment of giardiasis. However, clinical resistance of Giardia to metronidazole has been reported. Although several other drugs are currently available, new, potent, and selective (i.e., devoid of serious side effects) anti-parasitic medications are needed to combat resistance and improve efficacy. This project aims to develop such new drugs employing click chemistry, a strategy for rapid and efficient assembly of compounds with desired function. Additionally, click chemistry-based bioconjugation techniques will be used to study the mode of action of the active compounds. The screening libraries will be synthesized using catalytic azide-alkyne cycloadditions and will be assayed against both the wild type and the resistant Giardia strains. The straightforward syntheses we will employ guarantee rapid structure-activity profiling and improvement of the activity of the most promising leads. To study the mechanism of action of the active compounds, we will identify the covalent adducts of nitroazoles with Giardia proteins and will also study the differences in protein composition of the wild type and metronidazole-resistant Giardia strains. We will study electrochemically the formation of amino acid-metronidazole adducts and determine their exact chemical structures.

描述（由申请人提供）：贾第鞭毛疾病是由单细胞微观寄生虫，贾第鞭毛虫（Giardia intestinalis）（也称为贾第鞭毛虫兰布利亚）引起的水传播疾病的重要原因。致病性囊肿形式受外壳的保护，可以长时间在环境中生存。它耐水处理过程，例如臭氧解析和氯化。贾第鞭毛疾病被认为是源自饮用水和休闲水活动的水传播疾病最普遍的原因之一。贾迪亚在世界各地都发现了贾第鞭毛虫。此外，G。Lamblia是一种可信的生物恐怖主义威胁，因为它很容易获得，感染剂量很低，并且会引起严重的症状，例如腹痛，腹泻和恶心。甲硝唑是目前的贾第鞭毛虫病治疗。然而，贾第二亚甲硝唑对甲硝唑的临床抗性。尽管目前还有其他几种药物，但仍需要新的，有效和选择性（即缺乏严重的副作用）抗寄生虫药物来打击抵抗力并提高疗效。该项目旨在开发使用点击化学的新药，这是一种具有所需功能的化合物的快速和高效组装的策略。此外，单击基于化学的生物结合技术将用于研究活性化合物的作用方式。筛选文库将使用催化叠氮化物环载体合成，并将针对野生型和抗性贾第鞭毛虫菌株进行测定。我们将采用直接的合成，以确保快速的结构活性分析和最有希望的潜在客户活性的改善。为了研究活性化合物的作用机理，我们将确定硝基唑与贾第鞭毛虫蛋白的共价加合物，还将研究野生型和耐甲硝唑耐药的贾第鞭毛虫菌株的蛋白质组成差异。我们将在电化学上研究氨基酸 - 地酮加合物的形成，并确定其确切的化学结构。