Identification and Characterization of Novel Flavivirus Antivirals

黄病毒是许多对公共卫生有重要影响的疾病的病原体，包括韦氏 尼罗河脑炎、黄热病、登革热和日本脑炎。然而，目前的治疗方案 因为这些疾病是有限的，确实需要具有特定抗病毒活性的新的抗病毒药物 这些病毒。该项目的长期目标是通过识别和表征来满足这一需求 具有广谱抗重要医学病毒活性的新型小分子化合物。这个 我们提出的项目有三个具体目标。 具体目标1：高通量筛选鉴定新的先导化合物。 使用我们开发的西尼罗河病毒(WNV)病毒样颗粒(VLP)检测，这是合适的 对于在低生物遏制条件下使用，我们将对一个大型文库进行高通量筛选 区域英才中心国家筛选实验室的化合物。数据 将对筛选过程中产生的化合物进行分析，并确定最有希望的抗病毒化合物。这个 所选择的化合物对西尼罗河病毒的活性将通过活病毒检测和它们的广泛应用来证实。 在登革热病毒和黄热病病毒的活病毒检测中测定光谱抗黄病毒活性。 具体目标2：药物化学修饰和体外反复抗病毒试验。 根据它们对所有三种黄病毒的活性、毒性分布和化学修饰的可能性， 三种化合物将被确定为先导化合物，并将在 UTMB的平行合成和药物化学设施。每一轮化学修饰都将 涉及少量化合物的合成，这些化合物随后将经历快速的体外毒性和 活病毒检测中的抗病毒活性测试。这一过程将导致几轮受控迭代 我们期待的合成和评估将导致鉴定更有效的抗病毒化合物。 具体目标3：在活体内评价西尼罗河病毒脑炎小动物模型的活动性 在这一目标中，在化学修饰研究中确定的两种最有希望的化合物将是 使用西尼罗河病毒脑炎小鼠模型评估体内活性。 因此，到项目期结束时，我们预计将确定一些新的化合物，具有广泛的 对医学上重要的黄病毒的光谱活性，并已进行初步研究 在病毒学和病理学明确的动物模型中评估它们的潜在治疗效果 与临床情况相关的终结点。

Flaviviruses are the causative agents of a number of diseases of public health importance including West Nile encephalitis, yellow fever, dengue fever and Japanese encephalitis. However, current treatment options for these diseases are limited and there is a real need for new antiviral agents with specific activity against these viruses. The long-term objectives of this project are to meet this need by identifying and characterizing new small molecule compounds with broad spectrum activity against medically important f1aviviruses. The project that we propose has three specific aims. Specific Aim 1: High Throughput Screening Identification of Novel Lead Compounds. Using a West Nile virus (WNV) virus-like particle (VLP) assay that we have developed and, which is suitable for use under low bio-containment conditions we will conduct high-throughput screening of a large library of compounds at the National Screening Laboratory for the Regional Centers of Excellence. The data generated during screening will be analyzed and the most promising antiviral compounds identified. The activity of the selected compounds against WNV will be confirmed using live virus assays and, their broad spectrum anti-flavivirus activity determined in live virus assays with dengue virus and yellow fever virus. Specific Aim 2: Medicinal Chemistry Modification and Iterative in vitro Antiviral Testing. Based on their activity against all three flaviviruses, toxicity profiles and potential for chemical modification, three compounds will be identified as leads and will undergo a series of medicinal chemical modifications in the Parallel Synthesis and Medicinal Chemistry facility at UTMB. Each round of chemical modifications will involve the synthesis of a small number of compounds which will then undergo rapid in vitro toxicity and antiviral activity testing in live virus assays. This process will result in several rounds of controlled iterative synthesis and evaluation that we expect will lead to the identification of more potent antiviral compounds. Specific Aim 3: In Vivo Evaluation of Activity in a Small Animal Model of WNV Encephalitis In this aim the two most promising compounds identified during the chemical modification studies will be evaluated for activity in vivo using a mouse model of WNV encephalitis. Thus by the end of the project period we expect to have identified a number of new compounds with broad spectrum activity against medically important flaviviruses and to have undertaken preliminary studies to evaluate their potential therapeutic utility in a well defined animal model with virologic and pathologic endpoints that are relevant to those seen in the clinical situation.