ANTI-POXVIRUS NUCLEOSIDES:SYNTHESIS AND EVALUATION

描述（由申请人提供）：目前还没有被批准的抗病毒疗法，可以在使用痘病毒的生物恐怖袭击事件中快速部署，或者像猴痘病毒这样的本土病原体意外传播到世界其他地区。针对痘病毒感染的药物开发的最初努力集中在鉴定已经批准用于其他一些感染的化合物上。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，在体外是一种有效的痘病毒复制抑制剂，并且在动物模型感染中已被证明对痘苗病毒（VV）和牛痘病毒（CV）感染都非常有效。然而，它的肾毒性和口服可得性差限制了它的用途。因此，继续需要开发新的和更好的治疗痘病毒感染的模式。SBIR一期项目的具体目标是：1)合成新的嘧啶核苷系列（约30个），这些系列是根据b、C和D部分描述的原理设计的；2)与阿拉巴马大学伯明翰分校的Earl R. Kern教授合作，通过组织培养中的斑块减少试验评估这些核苷对VV和CV的抗病毒功效；3)确定铅化合物对VV和CV动物模型感染的功效，也与Kern教授合作。此外，化合物的体外和体内毒性将在内部以及与Kern博士合作确定。我们计划合成31种新的嘧啶核苷，用于组织培养系统的抗病毒评价。我们估计，根据我们的初步结果，四种化合物中的三种将在动物模型感染中具有足够的活性，并选择一种或两种候选化合物进行II期进一步开发。在II期，我们计划进一步研究在I期中选择的活性核苷在小动物和狗身上的详细临床前药理和毒理学特征，以用于IND应用。

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.