NEW INHIBITORS AND NEW TARGETS TO DEVELOP HCMV DRUGS

拟议研究的总体目标是设计、综合和 评价具有潜在抑制作用的新型杂环化合物 人巨细胞病毒感染。这将是一种全面的方法，包括 合成程序与体外生物的相互作用 评估计划，免疫学计划，体内评估核心 组件和行业合作者。主要的理由是 设计和合成将是有效和特定的抑制剂的化合物 人巨细胞病毒感染。这种专一性(选择性)将通过以下方式建立 评估化合物对其他病毒(如HSV-I)和正常的作用 哺乳动物细胞除人巨细胞病毒外。这些研究将提供反馈 合成程序，并允许合成努力保持专注 在那些有很高潜力提供化合物的区域 对人巨细胞病毒感染的抑制作用。 实现上述目标所依据的具体具体目标 已完成的内容在每个 实验室研究项目。这些目标可以概括为：1) 建立一个中央业务部门，以促进互动 以及研究项目与产业合作者之间的沟通 和NIAID工作人员；2)(实验室研究计划I)设计和 合成新型杂环化合物作为潜在的抗人巨细胞病毒药物 感染。综合努力将在一定程度上由 NCDDG生物部分的反馈；3)(实验室 研究计划II)评估新杂环化合物的活性 针对HCMV(减少斑块和滴度)，针对其他 病毒(如HSV I、HSV II等)、细胞毒性(HFF和KB细胞)以及 进行某些药物的体外代谢研究和抑制研究 目标酶或生物过程；4)(实验室研究方案 三)研究被认为具有活性的化合物的免疫学参数 按实验室研究计划II标准的巨细胞病毒制剂；5)(体内核心 组件)该实验室将在有限的 化合物的数量，选择是由 首席调查员、方案负责人和NIAID联络员；6) (行业协作)让行业协作者参与 关于将需要的适当研究的讨论和决定 对于正在进行体内评估的药物的进一步开发 舞台。

The overall goal of the proposed research is to design, synthesize and evaluate new heterocyclic compounds with potential for the inhibition of HCMV infections. This will be a comprehensive approach involving interactions between the synthesis program, the in vitro biological evaluation program, the immunological program, the in vivo evaluation core component and the industrial collaborator. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV infections. This specificity (selectivity) will be established by evaluating compounds against other viruses (e.g. HSV-I) and normal mammalian cells in addition to HCMV. These studies will provide feedback to the synthesis program and allow the synthetic efforts to remain focussed on those areas with a very high potential of providing compounds with inhibitory properties against HCMV infections. The detailed specific aims by which the above stated objectives will be accomplished are described in the specific sections for each of the laboratory research programs. These aims can be summarized as follows: 1) to establish a Central Operations Component to facilitate the interactions and communication between the research programs the industrial collaborator and the NIAID staff; 2) (Laboratory Research Program I) to design and synthesize new heterocyclic compounds as potential agents against HCMV infections. The synthetic efforts will be guided to a certain extend by feedback from the biological components of the NCDDG; 3) (Laboratory Research Program II) to evaluate new heterocyclic compounds for activity against HCMV (plaque reduction and titer reduction), activity against other viruses (e.g. HSV I, HSV II, etc.), cytotoxicity (HFF and KB cells) and to perform in vitro metabolism studies and inhibition studies of certain target enzymes or biological processes; 4) (Laboratory Research Program III) to study the immunologic parameters of compounds deemed to be active HCMV agents by Laboratory Research Program II's criteria; 5) (In vivo Core Component) this laboratory will perform in vivo evaluations on a limited number of compounds, the selection being made by a consensus of the Principal Investigator, Program Leaders and the NIAID liaison; 6) (Industrial Collaboration) to involve the industrial collaborator in discussions and decisions on the appropriate studies that will be needed for the further development of agents that are at the in vivo evaluation stage.