Disubstituted pyrimidine inhibitors of dengue virus entry

登革热病毒（DENV）是当今影响人类的最重要的蚊媒病毒性疾病。据估计，每年有1亿人感染登革热病毒，导致登革热和登革出血热。由于估计有25亿人生活在有流行病传播风险的地区，并且由于DENV感染的数量和导致登革出血热的感染比例在过去20年中都有所上升，缺乏抗DENV治疗药物或抗DENV疫苗是一个日益严重的公共卫生问题。我们最近发现了基于二取代嘧啶和α -酮氰腙支架的两个独立的DV进入抑制剂系列，它们似乎都阻断了病毒进入的融合步骤。在这里，我们建议利用药物化学、生物化学和病毒学的结合来了解这些化合物抗denv活性的结构-活性关系及其作用机制。

Dengue virus (DENV) is the most important mosquito-bome viral disease affecting humans today. An estimated 100 million people are infected with dengue virus annually, leading to dengue fever and dengue hemorrhagic fever (DHF). Since there are an estimated 2.5 billion people living in areas at risk for epidemic transmission and since both the number of DENV infections and the proportion of infections resulting in DHF have escalated in the past 20 years, the absence of anti-DENV therapeutics or an anti-DENV vaccine is a growing public health concern. We recently discovered two independent series of inhibitors of DV entry based on disubstituted pyrimidine and alpha-ketocyanohydrazone scaffolds, both of which appear to block the fusion step of virus entry. Here, we propose to utilize a combination of focused medicinal chemistry, biochemistry, and virology to understand the structure-activity relationships governing the anti-DENV activity of these compounds as well as their mechanism of action.