Drug Discovery Consortium for Chagas Disease

描述（由申请人提供）：本提案的目标是改变克氏锥虫药物开发的现状。我们建议建立一个由学术实验室和制药公司组成的联盟，他们将研究各种独立鉴定的药物靶点和候选化合物。具体来说，新型硝基三唑、类异戊二烯途径抑制剂、磷酸二酯酶抑制剂、蛋白酶抑制剂和半乳糖呋喃糖抑制剂的开发将由该联盟的学术和工业合作伙伴进行。靶标识别和验证以及化合物合成将在多个地点进行，依靠合作伙伴的特定专业知识来追求不同的线索。化合物文库或单个候选分子的筛选将使用一套严格的、经过良好验证的体外和体内分析来集中进行。咨询委员会由该联盟各项目的主任组成，并辅以外部专家，将每年举行两次会议，评估进展情况并确定测试和进一步开发的优先事项。这些会议也将成为联盟中学术和工业合作伙伴之间进一步合作的机会——这些类型的关系对于我们将作为这项研究的一部分进行的测试，以及在更大的动物，最终在人类身上进行进一步的先导优化、安全性和有效性试验是必要的。诸如在初始测试中证明的有效性、治疗指数、易于合成、衍生物库的可用性以及证明的安全性或事先许可用于人类等因素将决定哪些候选药物将在测试管道中进行，哪些将被放弃。此外，该联盟将接受其他合作伙伴的申请，这些合作伙伴的候选化合物针对被认为具有高度可药物性的靶标。联合疗法——将多种新发现的化合物直接用于不同的靶点，或将新化合物与目前使用的化合物结合使用，将被研究以确定在较短的治疗周期或较低剂量下有效的药物组合。恰加斯病是由原虫克氏锥虫感染引起的，被描述为“被忽视疾病中最被忽视的疾病”之一，在美洲影响多达2 000万人。这项提议的重点是发现和开发治疗这种感染的药物。

DESCRIPTION (provided by applicant): The goal of this proposal is to change this landscape in Trypanosoma cruzi drug development. We propose the development of a consortium of academic laboratories and pharmaceutical companies who will investigate a variety of independently identified drug targets and candidate compounds. Specifically, the development of novel nitrotriazoles, isoprenoid pathway inhibitors, phosphodiesterase inhibitors, protease inhibitors and inhibitors of galactofuranose will be pursued by the academic and industrial partners in this Consortium. Target identification and validation, and compound synthesis will be conducted at multiple sites, relying on the specific expertise of the partners to pursue distinct leads. Screens of compound libraries, or individual candidate molecules, will be conducted centrally using a set of rigorous, well-validated in vitro and in vivo assays. An Advisory Board consisting of the directors of the individual projects in the Consortium, and supplemented with outside experts, will meet twice yearly to assess progress and determine priorities for testing and further development. These meetings will also be opportunities for the development of further collaborations between the academic and industrial partners in the consortium - these types of relationships will be necessary to move beyond the testing we will conduct as part of this study and into further lead optimization, safety and efficacy trials in larger animals, and eventually, humans. Factors such as demonstrated efficacy in initial tests, therapeutic index, ease of synthesis, availability of derivative libraries, and demonstrated safety or prior licensing for use in humans will determine which candidates will move forward in the testing pipeline and which will be dropped. Additionally, the Consortium will entertain applications for additional partners with candidate compounds against targets that are judged to be highly druggable. Combination therapies- delivering multiple newly identified compounds directed at distinct targets or a combination of new compounds with compounds currently in use will be investigated to identify drug combinations which are effective using shorter treatment periods or lower doses. Chagas disease, the result of infection with the protozoan Trypanosoma cruzi, has been described as one of the "most neglected of the neglected diseases", affecting up to 20 million individuals in the Americas. The focus of this proposal is the discovery and development of drugs to treat this infection.