Development of Dynamic Combinatorial Libraries for Cruzipain Inhibition

描述（由申请人提供）：此福格蒂国际研究合作奖（FIRCA）的应用程序已被设计为扩大和加强母基金P01 CA 78039（项目PI Wipf，彼得），并扩大和增加外国科学家的研究能力（马勒博士，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。设计和合成新的支架以产生动态组合文库：（a）使用吡唑并三嗪酮和醛作为结构单元;（B）使用具有醛作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去卷积来鉴定抑制剂;（B）将对cruzipain显示亲和力的化合物提交用于体外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，以评价杀锥虫活性。生物测定将由阿根廷布宜诺斯艾利斯省圣马丁市圣马丁国立大学的Cazzulo教授进行。因此，这项建议和母赠款有着共同的目标，即开发动态组合方法来实现这些目标。由克氏锥虫引起的恰加斯病是拉丁美洲的一个重大公共卫生问题，是造成该地区最大寄生虫病负担的疾病之一。这种情况的治疗一直存在争议，但越来越多的共识是消除T。cruzi可能是阻止疾病发展的先决条件。目前可用的基于硝呋替莫和苯并咪唑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的有限功效和它们的毒副作用。特异性化疗的新方法正在推进;生化途径如cruzipain介导的蛋白水解已经在体外和体内抗T细胞的化学验证和选择性。已经证明了该途径抑制剂的Cruzi活性。该计划的主要目标的成功完成将为cruzipain抑制提供新的线索，并开辟了发现可用于恰加斯病的新药物样分子以及可用于生成动态组合库的新交换反应的可能性。由Tripanosoma cruzi引起的恰加斯病是拉丁美洲的一个主要公共卫生问题，它构成了最大的寄生虫病负担之一。这种情况的治疗一直存在争议，但越来越多的共识是消除T。cruzi可能是阻止疾病发展的先决条件。

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.