NUCLEOSIDES AS ANTI-ORTHOPOXVIRUS AGENTS

描述（改编自申请人摘要）：我们提出了一项研究， 进一步开发两类化合物作为潜在的抗痘病毒剂。 的 我们研究的先导化合物是碳环3-脱氮腺苷， 和有效的体外和体内抗牛痘病毒活性，以及N1- 芳烷氧基腺苷，其具有可重复的和有效的体外抗- 牛痘病毒活性，但尚未在体内进行检测。 体外 这两种先导化合物组的活性先前在一个 USAMRIID化合物对陆军感兴趣的病毒进行筛选，而 体内抗牛痘活性最近在USAMRIID研究中被观察到， 化合物作为潜在的抗痘病毒剂。 我们的努力对拟议的碳环3-deazaadenosine类似物将是 旨在优化其抗痘病毒活性以及 S-腺苷高半胱氨酸（SAH）水解酶抑制。 亲密的关系 在我们的先导化合物中， 其他核苷类似物的文献报道。 我们将 靶向新的碳环3-脱氮腺苷类似物和其它核苷 具有修饰的5-prime侧链的类似物，其可以与 水解酶口袋中的疏水和亲水基团， 与S-腺苷同型半胱氨酸的同型半胱氨酸相互作用。 我们对新的追求 我们的N1-芳烷氧基腺苷的类似物缺乏机理原理， 因此，我们将制备新的芳烷基类似物（杂环和 苄基）和环烷基，其可以帮助优化 它们的抗牛痘活性及其作用机制的阐明 将是共同的焦点。 我们所有目标化合物的合成将在SRI中进行。 较大 在我们的Prep中也可以合成大量的任何有希望的先导化合物。 laboratories. 未来目标的设计将是SRI和 和我们的合作者 USAMRIID的约翰·哈金斯博士、罗纳德·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用于抗痘病毒 活性及其SAH水解酶抑制。 斯图尔特·舒曼博士 斯隆凯特琳研究所将帮助我们集中精力， N1-芳烷氧基腺苷类似物的作用机制。

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.