Repurposing drugs to prevent and inhibit Zika virus inflections

项目总结和摘要 最近在波利尼西亚和巴西爆发的寨卡病毒（ZIKV）与不良神经系统疾病有关- 胎儿小头畸形和格林-巴利综合征-促使世界卫生组织宣布这种病毒 国际关注的突发公共卫生事件目前没有治疗ZIKV感染的疗法，并且 因此，迫切需要现成和安全的治疗选择。 我们发现了一种FDA批准的药物（代码SSZ），可以抑制Vero细胞（猴肾细胞系）中的ZIKV感染 缺乏干扰素信号传导）和原代胎盘Hofbauer细胞。SSZ被批准用于治疗关节炎 和消化系统疾病，具有良好的安全性。重要的是，SSZ是B类妊娠药物 因为在怀孕大鼠和兔子中进行的高剂量研究并未导致胎儿发育异常。这项建议 旨在进一步评估SSZ作为ZIKV单独治疗和与ZIKV联合治疗的安全临床前候选者。 其他活性剂。在本申请中提出了与正在进行的动物试验并行追求的两个目的。 在巴西学习。 目的1是描述SSZ在临床前和转化研究中的抗病毒活性。第一个目标是调查 在允许ZIKV感染的原代细胞中的SSZ抑制和安全性。列出了要评估的行，但 不限于感染部位的细胞（成纤维细胞、角质形成细胞和树突细胞）和中枢神经系统 系统（神经母细胞）。此外，将评估抑制动力学，以模拟潜在的治疗方式 正在进行临床试验这些结果将支持和平行正在进行的动物研究与合作者在 流行国家。SSZ将在与其他FDA批准的药物的联合研究中进一步评估， 最近发现具有抗ZIKV活性。 目的2试图确定SSZ是否主要通过病毒蛋白直接抑制ZIKV或通过宿主间接抑制ZIKV。 免疫救援负责病毒RNA复制和加工的病毒非结构蛋白5（NS 5） 和拮抗宿主免疫应答，并且初步数据表明SSZ结合ZIKV NS 5。SSZ可能 作为非核苷酸NS 5抑制剂，同时也拯救宿主免疫反应-双重宿主/病原体 作用机制。该项目概述的目标有望确定一种新的抗病毒机制， 采取行动重新利用FDA批准的安全药物，以快速应对正在进行的ZIKV爆发。

PROJECT SUMMARY AND ABSTRACT Recent outbreaks of Zika virus (ZIKV) in Polynesia and Brazil correlate with adverse neurological disorders – fetal microcephaly and Guillain-Barré syndrome – prompting the World Health Organization to declare this virus a public health emergency of international concern. No therapy is currently available to treat ZIKV infection, and it follows that there is an urgent need for readily available and safe treatment options. We discovered a FDA-approved drug (code SSZ) that inhibits ZIKV infection in Vero cells (a monkey kidney line devoid of interferon signaling) and primary placental Hofbauer cells. SSZ is approved for the treatment of arthritis and digestive disorders with a well-established safety profile. Importantly, SSZ is a category B pregnancy drug as high-dose studies in pregnant rats and rabbits did not cause abnormal fetal development. This proposal seeks to further evaluate SSZ as a safe pre-clinical candidate for ZIKV treatment alone and in combination with other active agents. Two aims are proposed in this application to be pursued in parallel with on-going animal studies in Brazil. Aim 1 is to profile the antiviral activity of SSZ in pre-clinical and translational studies. The first aim will investigate SSZ inhibition and safety in primary cells permissive to ZIKV infection. The lines to be evaluated are listed, but not limited to, cells at the site of infection (fibroblasts, keratinocytes and dendritic cells) and the central nervous system (neuroblasts). Additionally, inhibition kinetics will be assessed to model potential treatment modalities en route to clinical trials. These results will support and parallel on-going animal studies with collaborators in endemic countries. SSZ will be further evaluated in combination studies with other FDA-approved drugs that were recently found to possess anti-ZIKV activity. Aim 2 seeks to determine if SSZ primarily inhibits ZIKV directly through viral proteins or indirectly through host immune rescue. The viral non-structural protein 5 (NS5) responsible for viral RNA replication and processing and antagonizing host immune response, and preliminary data suggests that SSZ binds to ZIKV NS5. SSZ may act as a non-nucleotide NS5 inhibitor while also rescuing host immune response – a dual host/pathogen mechanism of action. The aims outlined in this project hold promise to identify a novel mechanism of antiviral action towards repurposing a safe FDA-approved drug in rapid response to the on-going ZIKV outbreak.