NEW CHEMICAL ENTITIES AND UNIQUE TARGETS FOR HCMV

所提出的研究的总体目标是设计、合成新的杂环化合物、核苷类似物及其前药，作为用于治疗疱疹病毒感染，特别是由人巨细胞病毒（HCMV）引起的疱疹病毒感染的潜在药物。 化合物的设计将基于我们最近发现的新的先导化合物和新的抗病毒靶点的证据。 后一项研究将基于初步数据，这些数据显示了新化合物的独特作用模式。总体方法将涉及两个合成项目之间的相互作用，体外生物学评价，病毒学和生物化学研究，以及体内评价加上初始毒理学和药代动力学。 主要的基本原理是设计和合成化合物，这将是有效的和特异性的HCMV复制抑制剂。实现这些目标的具体目标详见每个研究项目的具体目标部分。本研究的主要目的如下：1）研究项目1和2将设计和合成新的化合物和前药，作为治疗HCMV感染的潜在药物。 综合努力将以该方案生物组成部分的反馈为指导。 2)研究项目3将对新化合物的抗HCMV（空斑减少和产量减少）和单纯疱疹病毒1型（HSV-1）活性以及未感染细胞的细胞毒性进行初步评估。 该项目还将负责研究新的和现有的化合物的模式，以更好地了解它们的作用，并确定新的病毒药物靶点。 研究将包括体外药物代谢、某些靶酶或生物过程的抑制、分子生物学和病毒遗传学。 4)科学核心将提供针对其他人类疱疹病毒和动物疱疹病毒的新化合物的更广泛的体外评估，最有前途的新化合物的体内测试，以及初步毒理学和药代动力学评估。 通过这些方式，我们将为药物发现的关键初始阶段和重要艾滋病相关机会性感染的新疗法的开发提供全面的计划。

The overall goal of the proposed research is to design, synthesize new heterocyclic compounds, nucleoside analogs, and prodrugs thereof as potential drugs for the treatment of herpesvirus infections, particularly those caused by human cytomegalovirus (HCMV). Compound design will be based upon our recent discoveries of new lead compounds and on evidence for new antiviral targets. The latter studies will be based upon preliminary data which show a unique mode of action for new compounds. The overall approach will involve interactions among two synthesis projects, in vitro biological evaluation, virological and biochemical studies, and in vivo evaluation plus initial toxicology and pharmacokinetics. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV replication. The detailed specific aims by which these objectives will be accomplished are described in the specific aims section for each of the research projects. The aims can be summarized as follows: 1) Research Projects 1 and 2 will design and synthesize new compounds and prodrugs as potential agents for HCMV infections. The synthetic efforts will be guided by feedback from the biological components of the Program. 2) Research Project 3 will provide initial evaluation of new compounds for activity against HCMV (plaque reduction and yield reduction) and herpes simplex virus type 1 (HSV-1) as well as for cytotoxicity in uninfected cells. This project also will be responsible for investigating the mode of new and existing compounds to better understand their action and also to identify new viral drug targets. Studies will include in vitro drug metabolism, inhibition of certain target enzymes or biological processes, molecular biology, and viral genetics. 4) The Scientific Core will provide more extensive in vitro evaluation of new compounds against other human herpesviruses and animal herpesviruses, in vivo testing of the most promising new compounds, plus initial toxicology and pharmacokinetic evaluation. In these ways, we shall provide a comprehensive program for the critical initial phases of drug discovery and development of new therapies for an important AIDS-associated opportunistic infection.