Novel small molecule inhibitors of dengue replication

描述（由申请人提供）：鉴于全世界每年有5000多万人感染登革热，包括50万例更严重的登革热出血热病例，而且没有批准的疫苗或抗病毒药物可用，因此迫切需要新的抗病毒药物来治疗和控制登革热病毒。疫苗开发是有希望的，但面临着若干重大挑战，包括需要平衡对所有四种血清型病毒的保护，以避免抗体依赖性的感染增强和登革出血热的风险。一种既能抑制病毒复制又不会增加ADE风险的抗病毒药物，对公共卫生和政府储备生物防御准备都极有价值，因为它提供了一种控制疫情的手段。SIGA登革热项目的总体目标是开发一种小分子治疗药物，用于治疗和/或预防由登革热病毒引起的疾病。建立了一种灵敏、特异的高通量筛选（HTS）方法，用于评价SIGA化合物文库中化合物对登革热-2病毒复制的抑制活性。已确定的hit是有效的（EC50<5uM）和选择性的（CC50 bb0 25uM），在几个系列的相关化合物中具有初始的结构活性关系。铅系列将通过活性谱、作用机制、初步吸收、分布、代谢和排泄（ADME）谱和药代动力学（PK）评估来定义。根据生物学表征、相关类似物的化学可追溯性、化学信息学分析和初步结构活性关系的结果，将选择一到两个先导化合物系列进行化学优化，以产生临床前候选化合物。公共卫生相关性：SIGA登革热项目的总体目标是开发一种小分子治疗药物，用于治疗和/或预防由登革热病毒引起的疾病。

DESCRIPTION (provided by applicant): There is an urgent need for new antivirals for both treatment and control of dengue virus, given that over 50 million people are infected worldwide with dengue every year, including 500,000 cases of the more severe form of the disease, dengue hemorrhagic fever (DHF) and there are no approved vaccines or antiviral drugs available. Vaccine development is promising but faces several significant challenges including the need to balance protection against all four serotypes of the virus equally in order to avoid antibody-dependent enhancement of infection and risk of DHF. An antiviral drug that inhibits viral replication without increasing the risk for ADE would be extremely valuable for both public health by providing a means to control outbreaks, as well as to government stockpiles for biodefense preparedness. The overall goal of the SIGA dengue program is to develop a small molecule therapeutic for the treatment and/or prevention of disease caused by dengue virus. A sensitive and specific high throughput screening (HTS) assay has been developed to evaluate compounds from the SIGA chemical compound library for inhibitory activity against dengue-2 (DEN-2) virus replication. Hits have been identified that are potent (EC50<5uM) and selective (CC50>25uM), with initial structure activity relationship in several series of related compounds. Lead series will be defined by spectrum of activity, mechanism of action, preliminary absorption, distribution, metabolism, and excretion (ADME) profiles, and pharmacokinetic (PK) evaluations. Based upon the outcome of the biological characterizations, chemical tractability of related analogs, cheminformatic analyses, and nascent structure activity relationships, one or two lead compound series will be selected for chemical optimization to generate a preclinical candidate. PUBLIC HEALTH RELEVANCE: The overall goal of the SIGA dengue program is to develop a small molecule therapeutic for the treatment and/or prevention of disease caused by dengue virus. .