Antiviral therapeutics for flavivirus infections

描述(申请人提供)：鉴于全世界每年有5000多万人感染登革热，包括500,000例更严重的登革出血热(DHF)病例，而且目前还没有获得批准的疫苗或抗病毒药物，迫切需要新的抗病毒药物来治疗和控制登革热病毒。疫苗开发前景看好，但面临着几个重大挑战，包括需要平等地平衡对所有四种血清型病毒的保护，以避免依赖抗体增加感染和DHF的风险。一种在不增加ADE风险的情况下抑制病毒复制的抗病毒药物，通过提供一种控制疫情爆发的手段，以及政府用于生物防御准备的储备，对公共卫生来说将是极其有价值的。 SIGA登革热计划的总体目标是开发一种治疗和/或预防登革热病毒引起的疾病的小分子疗法。 建立了一种灵敏和特异的高通量筛选(HTS)方法来评价从SIGA化合物库中提取的化合物对登革2型病毒复制的抑制活性。已确定的HITS是有效的(EC50；lt；5um)和选择性(CC50&Gt；25um)，在几个相关化合物中具有初步的构效关系。根据活性光谱、作用机制(MOA)、初步吸收、分布、代谢和排泄(ADME)特性、初步生物药学特性和耐受性对质量HITS进行表征。根据这一特征，确定了两个铅系列，它们具有与抗登革热药物开发一致的最佳生物学特征。在这项应用中，将合成选定的高质量HITS的化学类似物，以改善化合物的性质，从而提名一名临床前候选人，该候选人将进入IND使能毒理学。

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 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. Quality hits were characterized for spectrum of activity, mechanism of action (MOA), preliminary absorption, distribution, metabolism and excretion (ADME) properties, preliminary biopharmaceutical properties, and tolerability. Based on this characterization two lead series were identified that have an optimal biological profile consistent with development of an anti-dengue drug. In this application chemical analogs of selected quality hits will be synthesized to improve the properties of the compounds leading to the nomination of a preclinical candidate which will enter into IND-enabling toxicology.