NUCLEOSIDES AS ANTI-ORTHOPOXVIRUS AGENTS

描述(根据申请者的摘要改编)：我们提议进行一项研究，以 进一步开发两类化合物作为潜在的抗痘病毒药物。这个 我们研究的先导化合物是碳环3-脱氮腺苷，它具有重复性 在体外和体内都有很强的抗痘病毒活性，而N1- 芳烷氧基腺苷，具有可重复性和体外抗肿瘤活性 痘苗病毒的活性，但还没有在体内检测。试管苗 这两个先导化合物基团的活性先前在一种 USAMRIID化合物对陆军感兴趣的病毒进行筛选，而在 最近在USAMRIID的一项研究中发现了体内抗牛痘活性 化合物作为潜在的抗痘病毒药物。 我们在碳环3-脱氮腺苷类似物方面的努力将是 旨在优化他们的抗痘病毒活性以及他们的 S-同型半胱氨酸腺苷水解酶抑制作用。一段亲密的关系 在我们的先导化合物和一些 文献中报道的其他核苷类似物。我们会的 靶向新型碳环3-脱氮腺苷类似物和其他核苷 具有修饰的5素侧链的类似物，可以与 水解酶口袋中的疏水和亲水基团通常 与S的同型半胱氨酸相互作用--腺苷同型半胱氨酸。我们对新事物的追求 我们的N1-芳基氧基腺苷的类似物缺乏机械原理，并且 因此，我们将制备新的芳烷基类似物(包括杂环和 )和环烷基团，这两种基团都有助于优化 它们的抗痘苗活性及其作用机制的研究进展 将是共同关注的焦点。 我们所有目标化合物的合成将在SRI进行。更大 我们还可以在我们的Prep中合成大量有希望的线索 实验室。未来目标的设计将是SRI的共同努力 以及我们的合作者小组。USAMRIID的John Huggins博士、Ronald T. 堪萨斯大学的Borchardt和Rega的Erik de Clercq博士 比利时的一个研究所将评估我们的化合物的抗痘病毒 SAH水解酶活性及其抑制作用。斯图尔特·舒曼博士 斯隆·凯特林研究所将通过专注于 N1-芳基氧基腺苷类似物的作用机理。

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.