COMBINED APPROACH TO TARGETED ANTI-HERPESVIRUS DRUGS

靶向抗疱疹病毒药物的综合方法

• 批准号: 3547092
• 负责人: DONALD M COEN
• 金额: $ 19.99万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3547092
• 关键词: Alphaherpesvirinae; Betaherpesvirinae; DNA directed DNA polymerase; Herpes simplex disease; Herpesviridae disease; antiviral agents; dihydroxypropoxymethylguanine; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme induction /repression; enzyme inhibitors; genetic manipulation; human tissue; mutant; nucleic acid chemical synthesis; nucleoside analog; peptide chemical synthesis; pharmacology; protein engineering; protein sequence; proteins; synthetic peptide; tissue /cell culture; virus genetics; virus infection mechanism; virus replication

The herpesviruses, herpes simplex virus (HSV) and human cytomegalovirus (CMV), are two important human pathogens for which there is a critical need to develop safe, effective antiviral agents. HSV is amenable to a variety of molecular and genetic tools that can be brought to bear on a problem. Concepts developed in the HSV system frequently are then applicable to CMV. The long term objective of the proposed research is to identify, characterize, and exploit drug targets of HSV and CMV. The existence of these targets is, or will be, inferred from mutants that exhibit altered sensitivity to previously existing drugs. The information derived from molecular characterization of these targets will be used to tailor new, more effective anti- herpesvirus drugs. This approach combines advantages of a random screening approach, which automatically selects targets for those kinds of small molecules that make useful drugs, and targeted approaches, in which molecular knowledge is used for drug design. Three classes of drugs will be developed. The first class will be synthetic peptides derived from the HSV DNA polymerase that disrupt the interaction of the HSV DNA polymerase and the major HSV DNA binding protein. The second class will be nucleoside analogs that are activated by a CMV function, newly identified by a drug resistant mutant, that contributes to the specific activation of ganciclovir (DHPG). The third class will be defined by the molecular characterization of drug targets identified by isolation and analysis of mutants of HSV and CMV that are resistant to drugs that act selectively against these viruses by unknown mechanisms.

疱疹病毒，单纯疱疹病毒（HSV）和人类 巨细胞病毒（CMV）是两种重要的人类病原体 这是开发安全，有效抗病毒的迫切需求 代理商。 HSV适合各种分子和遗传 可以解决问题的工具。 概念 然后，在HSV系统中经常开发 CMV。 拟议研究的长期目标是 识别，表征和利用HSV和CMV的药物靶标。 这些目标的存在是从或将从 对先前现有的敏感性改变的突变体 毒品。 从分子表征得出的信息 这些目标将用于量身定制新的，更有效的反抗 疱疹病毒药物。 这种方法结合了 随机筛选方法，该方法自动选择目标 对于那些制成有用药物的小分子， 有针对性的方法，其中分子知识用于 药物设计。 将开发三类药物。 头等舱将是 源自HSV DNA聚合酶的合成肽 破坏HSV DNA聚合酶和主要的相互作用 HSV DNA结合蛋白。 第二类将是核苷 通过CMV函数激活的类似物，新近识别 耐药突变体，有助于特定 Ganciclovir（DHPG）的激活。 将定义第三类 通过由药物靶标的分子表征 HSV和CMV突变体的隔离和分析 对通过有选择性作用于这些病毒的药物的抗药性 未知机制。