NUCLEOSIDES AS ANTI-ORTHOPOXVIRUS AGENTS

核苷作为抗正痘病毒剂

• 批准号: 6532839
• 负责人: JOHN A SECRIST
• 金额: $ 26万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532839
• 关键词: Poxviridae; antiviral agents; cooperative study; drug design /synthesis /production; nucleoside analog

DESCRIPTION (adapted from applicant's abstract): We are proposing a study to further develop two compound classes as potential antipoxvirus agents. The leads for our study are carbocyclic 3-deazaadenosine, which has reproducible and potent in vitro and in vivo anti-vaccinia virus activities, and N1- aralkyloxyadenosines, which have reproducible and potent in vitro anti- vaccinia virus activity, but have not yet been examined in vivo. The in vitro activities for both lead compounds groups were previously discovered in a USAMRIID compound screen against viruses of interest to the Army, while the in vivo anti-vaccinia activity has been recently seen in a USAMRIID study of compounds as potential antipoxvirus agents. Our efforts toward the proposed carbocyclic 3-deazaadenosine analogues will be directed toward optimizing both their antipoxvirus activities as well as their S-adenosylhomocysteine (SAH) hydrolase inhibition. A close relationship has been noted between these two properties in our lead compound and in a number of other nucleoside analogues reported in the literature. We will be targeting new carbocyclic 3-deazaadenosine analogues and other nucleoside analogues that have a modified 5-prime side chain that can interact with the hydrophobic and hydrophilic groups in the hydrolase pocket that normally interact with the homocysteine of S-adenosylhomocysteine. Our pursuit of new analogues of our N1-aralkyloxyadenosines lacks a mechanistic rationale, and thus, we will be preparing new analogues with aralkyl (both heterocyclic and benzylic) and cycloalkyl groups that can help in both the optimization of their anti-vaccinia activities and the elucidation of the mechanism of action will be joint focuses. The synthesis of all of our target compounds will be pursued in SRI. Larger quantities of any promising leads can also be synthesized in our Prep laboratories. The design of future targets will be a joint effort between SRI and our group of collaborators. Dr. John Huggins of USAMRIID, Dr. Ronald T. Borchardt of the University of Kansas, and Dr. Erik De Clercq of the Rega Institute in Belgium will be evaluating our compounds for their antipoxvirus activities and their SAH hydrolase inhibition. Dr. Stewart Shuman of the Sloan Kettering Research Institute will be helping us by concentrating on the mechanism of action of the N1-aralkyloxyadenosine analogs.

描述（改编自申请人的摘要）：我们正在提议一项研究 进一步开发两类化合物作为潜在的抗痘病毒剂。 这 我们研究的先导物是碳环 3-脱氮腺苷，它具有可重复性 和有效的体外和体内抗痘苗病毒活性，以及​​ N1- 芳烷氧基腺苷，具有可重复且有效的体外抗 牛痘病毒活性，但尚未在体内进行检查。 体外 先前在一个研究中发现了两个先导化合物组的活性 USAMRIID 针对陆军感兴趣的病毒进行复合筛选，而在 最近在 USAMRIID 的一项研究中发现了体内抗痘苗活性 化合物作为潜在的抗痘病毒剂。 我们对所提议的碳环3-脱氮腺苷类似物的努力将是 旨在优化其抗痘病毒活性及其 S-腺苷高半胱氨酸（SAH）水解酶抑制。 密切的关系有 在我们的先导化合物和一些化合物中已经注意到这两种特性之间的关系 文献中报道的其他核苷类似物。 我们将会 靶向新的碳环3-脱氮腺苷类似物和其他核苷 具有修饰的 5 素数侧链的类似物，可以与 水解酶袋中的疏水基团和亲水基团通常 与S-腺苷同型半胱氨酸相互作用。 我们追求新 我们的 N1-芳烷氧基腺苷的类似物缺乏机制原理，并且 因此，我们将用芳烷基（杂环和 苄基）和环烷基，可以帮助优化 它们的抗痘苗活性及其作用机制的阐明 将成为共同焦点。 我们所有目标化合物的合成都将在 SRI 中进行。 较大 任何有希望的先导化合物的数量也可以在我们的 Prep 中合成 实验室。 未来目标的设计将由SRI与SRI共同努力 以及我们的合作者团队。 USAMRIID 的 John Huggins 博士、Ronald T. 堪萨斯大学的 Borchardt 和 Rega 的 Erik De Clercq 博士 比利时的研究所将评估我们的化合物的抗痘病毒作用 活性及其 SAH 水解酶抑制作用。 斯图尔特·舒曼博士 斯隆凯特琳研究所将通过专注于以下方面来帮助我们 N1-芳烷氧基腺苷类似物的作用机制。