Repurposing drugs to prevent and inhibit Zika virus inflections

重新利用药物来预防和抑制寨卡病毒感染

• 批准号: 9269708
• 负责人: Raymond Felix Schinazi
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-08 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269708
• 关键词: Aedes; Affect; Africa; Animal Model; Animals; Antibodies; Antiviral Agents; Arthralgia; Arthritis; Asia; Asians; Azulfidine; B-Lymphocytes; Binding; Bioavailable; Biological Assay; Biological Availability; Biological Markers; Blood; Brain; Brain Neoplasms; Brazil; Categories; Cell Line; Cell model; Cells; Cellular Assay; Central America; Clinical; Clinical Data; Clinical Trials; Code; Country; Coupled; Data; Dendritic Cells; Dengue; Digestive System Disorders; Disease Outbreaks; Dose; Enhancers; Epilepsy; Evaluation; Exanthema; Exhibits; FDA approved; Fetal Development; Fetal Diseases; Fever; Fibroblasts; Flavivirus; Guillain-Barré Syndrome; Hamsters; Headache; Hepatitis C; Human; Immune; Immune response; Individual; Infection; Interferon Activation; Interferons; International; Japanese encephalitis virus; Kidney; Kinetics; Laboratories; Light; Maintenance; Mediating; Microcephaly; Modality; Modeling; Monitor; Monkeys; Mutation; Neuraxis; Neurological outcome; Newborn Infant; Norwalk virus; Nuclear; Nuclear Translocation; Oral; Oryctolagus cuniculus; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Placenta; Plasma; Polynesia; Positioning Attribute; Pregnancy; Pregnancy Outcome; Pregnant Women; Preventive therapy; Property; Puerto Rico; RNA; RNA Processing; RNA Viruses; RNA replication; Rattus; Replicon; Reporting; Resistance; Route; Safety; Salicylic Acids; Seizures; Signal Transduction; Site; Site-Directed Mutagenesis; South America; Sulfasalazine; Support System; Symptoms; Testing; Therapeutic Agents; Toxic effect; Uganda; United States; Vero Cells; Vertebrates; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; West Nile virus; World Health Organization; Zika Virus; base; brain abnormalities; cell type; clinical candidate; clinically relevant; combat; fetal; in vivo; inhibitor/antagonist; insight; keratinocyte; kidney cell; maternal serum; mouse model; nervous system disorder; neuroblast; novel; pathogen; permissiveness; polymerization; pre-clinical; preclinical study; pregnant; prevent; public health emergency; response; small molecule; time use; translational study; treatment response; vector mosquito; viral RNA; viral rebound

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.

项目摘要和摘要 波利尼西亚和巴西的寨卡病毒（ZIKV）最近暴发与不良神经系统疾病相关 - 胎儿小头畸形和Guillain-Barré综合征 - 促使世界卫生组织宣布这种病毒 国际关注的公共卫生紧急情况。目前尚无治疗ZIKV感染的治疗，并且 因此，迫切需要随时可用且安全的治疗选择。 我们发现了FDA批准的药物（代码SSZ），该药物抑制了Vero细胞中的ZIKV感染（猴子肾脏线 没有干扰素信号传导）和原发性斑点霍夫鲍尔细胞。 SSZ被批准用于治疗关节炎 以及具有良好安全性的消化障碍。重要的是，SSZ是B类怀孕药物 由于对怀孕大鼠和兔子的高剂量研究并未引起胎儿发育异常。这个建议 寻求进一步评估SSZ作为单独ZIKV治疗的安全临床前候选者 其他活性代理。在本申请中提出了两个目标，将与持续的动物并行追求 巴西的研究。 目的1是在临床前和翻译研究中介绍SSZ的抗病毒活性。第一个目标将调查 原代细胞的SSZ抑制和安全性允许ZIKV感染。列出了要评估的行，但是 不限于感染部位的细胞（成纤维细胞，角质形成细胞和树突状细胞）和中枢神经 系统（神经细胞）。此外，将评估抑制动力学以模拟潜在的治疗方式 在临床试验的途中。这些结果将支持并与正在进行的动物研究与合作者进行 内在国家。 SSZ将在与其他FDA批准的药物的组合研究中进一步评估 最近发现具有抗ZIKV活性。 AIM 2试图确定SSZ主要是直接通过病毒蛋白或间接抑制ZIKV 免疫救援。病毒非结构蛋白5（NS5）负责病毒RNA复制和加工 拮抗宿主免疫反应，初步数据表明SSZ与ZIKV NS5结合。 SSZ可能 充当非核苷酸NS5抑制剂，同时还挽救宿主免疫反应 - 双宿主/病原体 作用机理。该项目中概述的目的有望确定一种新颖的抗病毒药机制 在对正在进行的ZIKV爆发的迅速反应中，重新利用安全FDA批准的药物的行动。