Antiviral therapeutics for flavivirus infections

描述（由申请人提供）：鉴于每年全世界有超过5000万人感染登革热，包括50万例更严重的登革热出血热（DHF），并且没有批准的疫苗或抗病毒药物，因此迫切需要新的抗病毒药物用于治疗和控制登革热病毒。疫苗开发是有希望的，但面临着几个重大挑战，包括需要平衡对所有四种血清型病毒的保护，以避免抗体依赖性感染增强和DHF风险。一种抑制病毒复制而不增加ADE风险的抗病毒药物，通过提供控制疫情的手段以及政府生物防御准备的库存，对公共卫生极为宝贵。 SIGA登革热项目的总体目标是开发一种用于治疗和/或预防登革热病毒引起的疾病的小分子治疗剂。 已经开发了一种灵敏且特异的高通量筛选（HTS）测定来评估来自SIGA化合物库的化合物对登革-2（DEN-2）病毒复制的抑制活性。已鉴定出具有强效（EC 50 <5 uM）和选择性（CC 50> 25 uM）的命中物，在几个系列的相关化合物中具有初始结构活性关系。对活性谱、作用机制（MOA）、初步吸收、分布、代谢和排泄（ADME）特性、初步生物制药特性和耐受性进行了定性。基于该表征，鉴定了两个先导系列，其具有与抗登革热药物的开发一致的最佳生物学特性。在本申请中，将合成选定质量命中的化学类似物，以改善化合物的性质，从而提名临床前候选物，该候选物将进入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.