NEW CHEMICAL ENTITIES AND UNIQUE TARGETS FOR HCMV

本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，作为治疗疱疹病毒感染的潜在药物，特别是由人类巨细胞病毒（HCMV）引起的感染。化合物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。后一项研究将以初步数据为基础，这些数据显示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，体外生物学评估，病毒学和生化研究，以及体内评估加上初始毒理学和药代动力学。主要原理是设计和合成有效的特异性抑制HCMV复制的化合物。每个研究项目的具体目标部分描述了实现这些目标的具体目标。项目1和项目2将设计和合成新的化合物和前药，作为HCMV感染的潜在药物。2)研究项目3将对新化合物抗HCMV（斑块减少和产量减少）和1型单纯疱疹病毒（HSV-1）的活性以及对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)科学核心将提供更广泛的新化合物对抗其他人类疱疹病毒和动物疱疹病毒的体外评估，最有希望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，我们将为一种重要的艾滋病相关机会性感染的药物发现和新疗法开发的关键初始阶段提供一个全面的计划。

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.