Trypanosome Drug Development Consortium

描述（由申请人提供）：该项目旨在产生一个强大的抗锥虫药物管道，其产品概况适合临床试验和部署。它将由一个组织严密的锥虫药物开发联盟（TDDC）进行，该联盟拥有广泛和多样化的专业知识、技术能力、设施，并正在对这些病原体进行研究。TDDC联盟包括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爱斯基提斯研究所，每个研究所都与其他各种公共和私人机构建立了合作或咨询关系。该联盟拥有必要的技术和设备、化合物和天然产物库、体外和体内模型、专业知识和项目管理技能来开展该项目。它将使用基于里程碑的、决策矩阵支持的产品开发方法：1)通过综合文献和信息分析确定锥虫候选药物靶点，并将其优先用于实验验证和初始分析开发。2)为优先目标开发高通量筛选（HTSs）。HTSs将使用敏感和特异性的报告系统，通常使用重组蛋白，并且将是健壮的、可重复的和敏感的。3)筛选含有这些HTSs的合成和天然产物化合物文库，并进行锥虫细胞活力测定。将分离天然产物中的活性化合物并确定其结构，并确定所有有希望的产物的ic50。4)使用化合物类似物对先导物进行化学反应，提供高质量的候选先导物，迭代先导物优化和SAR分析。5)类铅化合物将进行功效和毒理学、ADME和PK测试，以产生一组可用于临床分析的化合物。6)建立一个集中的项目和信息管理系统，作为各场址之间以信息为基础的接口和社区资源。它将促进工作流程，帮助协调和决策。结果将是一组靶点和化学实体分布在从靶点发现到临床前验证的管道中，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.