NEW INHIBITORS AND NEW TARGETS TO DEVELOP HCMV DRUGS

拟议研究的总体目标是设计、合成和 评价新的杂环化合物具有抑制 HCMV感染。 这将是一个全面的办法， 合成程序、体外生物学 评价程序，免疫学程序，体内评价核心 组件和工业合作者。 主要理由是 设计和合成化合物， 巨细胞病毒感染。 该特异性（选择性）将通过以下方法确定： 评价化合物对其它病毒（例如HSV-I）和正常病毒的作用 哺乳动物细胞，除了HCMV。 这些研究将提供反馈 合成计划，并允许合成工作保持专注 在那些具有很高潜力的地区提供化合物， 抗HCMV感染的抑制特性。 上述目标的详细具体目标将 完成的工作在每一个具体章节中进行了描述， 实验室研究计划。 这些目标可以概括如下：1） 建立一个中央行动部分，以促进互动， 以及研究项目与工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 合成新杂环化合物作为抗HCMV的潜在药物 感染. 综合努力将在一定程度上受到以下方面的指导： 来自NCDDG生物组件的反馈; 3）（实验室 研究计划II），以评估新的杂环化合物的活性 抗HCMV（空斑减少和滴度降低）、抗其他 病毒（例如HSV I、HSV II等），细胞毒性（HFF和KB细胞）和 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）（实验室研究计划 III）研究被认为具有活性的化合物的免疫学参数 通过实验室研究计划II的标准的HCMV试剂; 5）（体内核心 组件）该实验室将对有限的 许多化合物，选择是由一个共识， 主要研究者、项目负责人和NIAID联络人; 6） （工业合作）让工业合作者参与 讨论和决定将需要进行的适当研究 为了进一步开发在体内评价的药剂， 阶段

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.