ANTI-POXVIRUS NUCLEOSIDES:SYNTHESIS AND EVALUATION

描述(申请人提供)：目前还没有批准的抗病毒疗法，可以在发生使用痘病毒的生物恐怖主义袭击或猴痘病毒等本土病原体意外传播到世界其他地区的情况下迅速部署。治疗痘病毒感染的药物开发的初步努力集中在鉴定已被批准用于某些其他感染的化合物。目前最好的候选药物是西多福韦，它被批准用于治疗某些巨细胞病毒感染，是一种有效的体外复制痘病毒的抑制剂，并已被证明在动物模型感染中对牛痘病毒(VV)和牛痘病毒(CV)感染都非常有效。然而，它的肾毒性和较差的口服利用度限制了它的用途。因此，仍然需要开发新的和更好的治疗痘病毒感染的模式。这个SBIR第一阶段项目的具体目标是：1)合成新的系列嘧啶核苷(约30个)，这些核苷是根据B.C和D节所述的基本原理设计的；2)与伯明翰阿拉巴马大学的Earl R.Kern教授合作，通过组织培养中的空斑减少试验评估这些核苷对VV和CV的抗病毒效力；以及3)与Kern教授合作，确定先导化合物在VV和CV动物模型感染中的有效性。此外，这些化合物的体外和体内毒性将在内部以及与克恩博士的合作下进行测定。我们计划合成31个新的嘧啶核苷，用于组织培养系统的抗病毒评估。根据我们的初步结果，我们估计四个化合物中的三个在动物模型感染中将具有足够的活性，并选择一个或两个候选化合物在第二阶段进一步开发。在第二阶段，我们计划进一步研究那些在第一阶段选择的活性核苷，用于IND应用于小动物和狗的详细临床前药理学和毒理学特征。

DESCRIPTION (provided by applicant): There are currently no approved antiviral therapies that could be rapidly deployed in the event of a bioterrorism attack using a poxvirus or the unexpected spread of an indigenous agent like monkey poxvirus to other parts of the world. Initial efforts in drug development for poxvirus infections have focused on the identification of compounds that are already approved for use in some other infection. The best candidate currently is cidofovir, which is approved for treatment of certain cytomegalovirus infections, is a potent inhibitor of poxvirus replication in vitro and has been shown to be very effective against both vaccinia virus (VV) and cowpox virus (CV) infections in animal model infections. Its nephrotoxicity and poor oral availability, however, limit its usefulness. Therefore, there is a continued need to develop new and better modes of therapy for Poxvirus Infection. The specific aims of this SBIR Phase I project are to: 1) Synthesize new series of pyrimidine nucleosides (about 30), which are designed on the basis of rationale described in the sections B. C and D; 2) Evaluate the antiviral efficacy of these nucleosides against VV and CV by plaque reduction assay in tissue culture in collaboration with Prof. Earl R. Kern of the University of Alabama at Birmingham; and 3) Determine the efficacy of lead compounds in animal model infections of VV and CV, also in collaboration with Professor Kern. In addition, the in vitro and in vivo toxicity of the compounds will be determined in-house as well as in collaboration with Dr. Kern. We plan to synthesize 31 novel pyrimidine nucleosides for antiviral evaluation in tissue culture systems. We estimate, based on our preliminary results, that three of four compounds will have sufficient activity in the animal model infections and select one or two candidates for further development in Phase II. In Phase II, we plan to further investigate those active nucleosides selected in Phase I for their detailed preclinical pharmacological and toxicological features in small animals and dogs for IND application.