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）：该Fogarty国际研究合作奖（FIRCA）申请旨在扩大和增强父母的赠款P01 CA78039（Project Pi Wipf，Peter，Peter Project），并扩大和提高外国科学家（Mahler，S。Graciela，S。Graciela）的研究能力，并提高外国学会和外国机构（Montevidevide），Montevidevidevidevidevideco uluguay）。具体目的是：1。新脚手架的设计和合成以生成动态组合库：（a）使用吡唑唑烷酮和醛作为组成部分； （b）使用带有醛的新杂环系统作为构建块。 2。识别具有生物学意义的化合物对Chagas疾病的意义：（a）使用Cruzipain酶测试文库，以通过动态反卷积的变化来鉴定抑制剂； （b）表现出与cruzipain亲和力的化合物将提交体外cruzipain抑制作用； （c）具有良好抑制活性的化合物将在体外提交给克氏锥虫的生长抑制测定法，以评估锥虫活性。该生物测定法将由阿根廷省圣马丁市圣马丁大学的Cazzulo教授进行。因此，该提案和父母的授予共享与发展这些目标的动态组合方法的发展有关的共同目标。由Cruzi引起的Chagas病是拉丁美洲的主要公共卫生问题，它构成了最大的寄生虫负担之一。这种情况的治疗是有争议的，但是越来越多的共识是，消除克鲁西氏菌可能是阻止这种疾病进化的先决条件。目前，基于Nifurtimox和Benznidazol的化学疗法是不令人满意的，因为它们在疾病的流行慢性阶段及其有毒副作用有限。采用特定化学疗法的新方法正在进行；诸如Cruzipain介导的蛋白水解之类的生化途径已在体外和体内抗T化学验证和选择性。已经证明了该途径抑制剂的克鲁兹活动。成功完成该计划的主要目的将为Cruzipain抑制作用提供新的潜在客户ABD的可能性，可以找到一种有用的类似药物的分子，以及在Chagas病中有用的，以及新的交换反应，对生成动态组合库的chagas病chagas疾病有用，这是由Cruzi造成的主要公共健康问题，是该疾病的主要公共健康问题。这种情况的治疗是有争议的，但是越来越多的共识是，消除克鲁西氏菌可能是阻止这种疾病进化的先决条件。