Trypanosome Drug Development Consortium

描述(由申请人提供)：该项目旨在产生一条强大的抗锥虫病药物流水线，其产品概况适合临床试验和部署。它将由一个高度组织的锥虫药物开发联盟(TDDC)进行，该联盟具有广泛和多样化的专业知识、技术能力、设施和正在进行的对这些病原体的研究。TDDC财团包括SBRI/华盛顿大学、加州大学旧金山分校、北卡罗来纳大学教堂山分校和格里菲斯大学埃斯基蒂斯研究所，每个机构都与其他各种公共和私人机构建立了合作或咨询关系。该财团拥有开展该项目所需的基本技术和设备、化合物和天然产品库、体外和体内模型、专业知识和项目管理技能。它将使用一种基于里程碑、决策矩阵支持的产品开发方法来：1)通过全面的文献和信息分析确定锥虫候选药物靶标，并将它们排在实验验证和初步化验开发的优先顺序。2)开发针对优先目标的高通量筛选(HTS)。HTSS将使用敏感和特定的报告系统，通常与重组蛋白一起使用，并且将是强大的、可重复性的和敏感的。3)筛选合成产物和天然产物的文库，并进行锥虫细胞活性测定。天然产物HITS中的活性化合物将被分离并确定其结构，所有有希望的HITS将被确定IC50。4)进行Hit-to-Lead化学以提供高质量的Lead候选者，并使用化合物类似物进行迭代的Lead优化和SAR分析。5)将对类铅化合物进行有效性和毒理学、ADME和PK测试，以产生一组精选的化合物用于临床分析。6)建立一个中央项目和信息管理系统，作为各地点之间的信息接口和社区资源。它将促进工作流程，并帮助协调和决策。结果将是一套从靶标发现到临床前验证的靶标和化学实体，从而为临床研究提供丰富的候选药物资源。

DESCRIPTION (provided by applicant): The project is designed to generate a robust pipeline of anti-trypanosomatid drugs with product profiles suitable for clinical trials and deployment. It will be conducted by a highly organized Trypanosomatid Drug Development Consortium (TDDC) with extensive and diverse expertise, technical capabilities, facilities, and ongoing studies with these pathogens. The TDDC consortium includes SBRI/University of Washington, UCSF, University of North Carolina at Chapel Hill, and the Eskitis Institute of Griffiths University, each of which has collaborative or consulting ties with various other public and private institutions. The consortium has the essential technologies and equipment, compound and natural product libraries, in vitro and in vivo models, expertise, and project management skills to conduct the project. It will use a milestone based, decision matrix supported, product development approach to: 1) Identify trypanosomatid candidate drug targets by comprehensive literature and informatic analyses and prioritize them for experimental validation and initial assay development. 2) Develop high throughput screens (HTSs) for prioritized targets. The HTSs will use sensitive and specific reporter systems, typically with recombinant proteins, and will be robust, reproducible, and sensitive. 3) Screen selected libraries of synthetic and natural product compounds with these HTSs as well as trypanosomatid cell viability assays. Active compounds in natural product hits will be isolated and their structures determined, and IC50s will be determined for all promising hits. 4) Perform hit-to lead chemistry to provide high-quality lead candidates and iterative lead optimization and SAR analysis using compound analogs. 5) Lead-like compounds will be tested for efficacy and toxicology, ADME, and PK to generate a select set of compounds for clinical analyses. 6) Generate a centralized project and information management system that will be instituted as an information-based interface among the sites and as a community resource. It will facilitate workflow and aid coordination and decision making. The outcome will be a set of targets and chemical entities distributed along the pipeline from target discovery to preclinical validation thus providing a rich ongoing resource of drug candidates for clinical studies.