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（根据申请人的摘要改编）：我们正在提出一项研究 进一步开发两个化合物类别作为潜在的抗氧化病毒药物。 这 我们研究的潜在客户是碳环糖3-二腺苷，具有可重现的 以及在体外和体内抗Vaccinia病毒活性以及N1- 芳香氧添合剂，具有可再现和有效的体外抗 疫苗病毒活性，但尚未在体内检查。 体外 以前在A中发现了这两个铅化合物组的活动 USAMRIID复合屏幕针对军队感兴趣的病毒，而IN 在USAMRIID的研究中，已经看到了体内抗疫苗的活性 化合物是潜在的抗氧化病毒药物。 我们为拟议的碳环环3-二腺苷类似物所做的努力将是 致力于优化其抗氧化病毒活动及其 S-腺苷类药物半胱氨酸（SAH）水解酶抑制。 亲密关系有 在我们的铅化合物中的这两个属性和数字中都注意到了 文献中报道的其他核苷类似物。 我们会的 靶向新的碳环糖3-二核类似物和其他核苷 具有修改的5-prime侧链的类似物可以与 水解酶袋中的疏水和亲水基团通常 与S-腺基质型半胱氨酸的同型半胱氨酸相互作用。 我们追求新的 我们的N1-芳基羟基丙烯剂的类似物缺乏机械原理，并且 因此，我们将准备使用aralkyl的新类似物（杂环和 苯并烷基和环烷基基团，可以有助于优化 他们的抗疫苗活动和作用机理的阐明 将是联合重点。 我们所有目标化合物的合成将在SRI中追求。 更大 在我们的准备中也可以合成任何有前途的潜在客户的数量 实验室。 未来目标的设计将是SRI之间的共同努力 和我们的合作者小组。 Usamriid的John Huggins博士，Ronald T.博士 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反毒素化合物 活动及其SAH水解酶抑制。 斯图尔特·舒曼博士 斯隆·凯特林研究所（Sloan Kettering Research Institute）将通过专注于我们 N1-芳基氧化丙烯类类似物的作用机理。