Development of Dynamic Combinatorial Libraries for Cruzipain Inhibition

Cruzipain 抑制动态组合文库的开发

• 批准号: 7462303
• 负责人: Peter Wipf
• 金额: $ 5.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462303
• 关键词: Adverse effects; Affinity; Aldehydes; Anthelmintics; Antimitotic Agents; Antineoplastic Agents; Area; Argentina; Award; Biochemical; Biochemistry; Biological; Biological Assay; Biological Factors; Chagas Disease; Chronic; Class; Collaborations; Condition; Consensus; Cytotoxic agent; Development; Disease; Doctor of Philosophy; Endopeptidases; Enzymes; Equilibrium; Evolution; Generations; Goals; Growth; Human; In Vitro; Institution; International; Laboratories; Laboratory Research; Latin America; Lead; Libraries; Ligands; Mediating; Methodology; Methods; Microtubules; Nifurtimox; Organic Synthesis; Parasites; Parasitic Diseases; Parasitology; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Play; Postdoctoral Fellow; Preparation; Process; Protein Phosphatase Inhibitor; Proteolysis; Protocols documentation; Public Health; Reaction; Research; Research Personnel; Role; Route; Scientist; Screening procedure; Solid; Solutions; Staging; System; Technology; Testing; Time; Trypanosoma cruzi; Universities; Uruguay; Work; analog; base; carbonyl compound; chemotherapy; combinatorial; combinatorial chemistry; cruzipain; design; in vitro Assay; in vivo; inhibitor/antagonist; inorganic phosphate; instrumentation; mimetics; novel; novel strategies; parent grant; professor; programs; scaffold

DESCRIPTION (provided by applicant): This Fogarty International Research Collaboration Award (FIRCA) application has been designed to expand and enhance the parent grant P01 CA78039 (Project PI Wipf, Peter), and to expand and increase the research capacity of the foreign scientist (Dr. Mahler, S. Graciela) and the foreign institution (University of the Republic, Montevideo Uruguay). Specific aims are: 1. Design and synthesis of new scaffolds to generate dynamic combinatorial libraries: (a) using pyrazolotriazinones and aldehydes as building blocks; (b) using new heterocyclic systems with aldehydes as building blocks. 2. Identify compounds with biological significance for Chagas disease: (a) test the libraries using the enzyme cruzipain in order to identify inhibitors by changes in the library distributionor by dynamic deconvolution; (b) compounds showing affinity to cruzipain will be submitted for in vitro cruzipain inhibition; (c) compounds having good inhibition activities will be submitted to a Trypanosoma cruzi growth inhibition assay in vitro, in order to evaluate the trypanocidal activity. The biological assay will be carried out by Prof. Cazzulo at Universidad Nacional de San Martin, San Martin, Provincia de Buenos Aires, Argentina. This proposal and the parent grant thus share common goals related to the development of dynamic combinatorial methodologies to achieve these objectives. Chagas disease, caused by Tripanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. The treatment of this condition has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease. Currently available chemotherapy, based on a nifurtimox and benznidazol, is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. New approaches to specific chemotherapy are being advanced; biochemical routes like cruzipain-mediated proteolysis have been chemically validated and selective in vitro and in vivo anti-T. cruzi activities of inhibitors of this pathway have been demonstrated. Successful completion of the major aims of this program will provide a new lead in cruzipain inhibition abd open up the possibility to find a new drug-like molecule useful in Chagas disease as well as new exchange reactions useful for the generation of dynamic combinatorial libraries Chagas disease, caused by Tripanosoma cruzi, is a major public health problem in Latin America, where it constitutes one of the largest parasitic disease burdens. The treatment of this condition has been controversial, but there is a growing consensus that elimination of T. cruzi could be a prerequisite to arrest the evolution of the disease.

描述（由申请人提供）：此福格蒂国际研究合作奖（FIRCA）申请旨在扩大和增强母基金 P01 CA78039（项目 PI Wipf，Peter），并扩大和提高外国科学家的研究能力（ Mahler 博士、S. Graciela）和外国机构（乌拉圭蒙得维的亚共和国大学）。具体目标是： 1. 设计和合成新支架以生成动态组合库： (a) 使用吡唑并三嗪酮和醛作为构建模块； (b) 使用以醛为结构单元的新杂环系统。 2. 鉴定对恰加斯病具有生物学意义的化合物： (a) 使用 cruzipain 酶测试文库，以便通过文库分布的变化或通过动态解卷积来鉴定抑制剂； (b) 显示对 cruzipain 亲和力的化合物将被提交用于体外 cruzipain 抑制； (c)将具有良好抑制活性的化合物进行体外克氏锥虫生长抑制测定，以评估杀锥虫活性。生物检测将由阿根廷布宜诺斯艾利斯省圣马丁国立大学的 Cazzulo 教授进行。因此，该提案和母基金具有与开发动态组合方法以实现这些目标相关的共同目标。由克氏锥虫引起的恰加斯病是拉丁美洲的一个主要公共卫生问题，也是拉丁美洲最大的寄生虫病负担之一。这种疾病的治疗一直存在争议，但越来越多的人认为消灭克氏锥虫可能是阻止这种疾病进化的先决条件。目前可用的基于硝呋替莫和苯硝唑的化疗并不令人满意，因为它们在疾病流行的慢性阶段的疗效有限且具有毒副作用。特定化疗的新方法正在开发中； cruzipain 介导的蛋白水解等生化途径已在体外和体内经过化学验证并具有选择性。该途径抑制剂的 cruzi 活性已得到证实。该计划主要目标的成功完成将为 cruzipain 抑制提供新的领先优势，并开辟寻找可用于恰加斯病的新药物样分子以及可用于生成恰加斯病动态组合文库的新交换反应的可能性由克氏锥虫引起的寄生虫病是拉丁美洲的一个主要公共卫生问题，是拉丁美洲最大的寄生虫病负担之一。这种疾病的治疗一直存在争议，但越来越多的人一致认为，消灭克氏锥虫可能是阻止这种疾病进化的先决条件。