New Use of Old Drugs for Zika Virus

老药新用途对抗寨卡病毒

基本信息

批准号：
9412543
负责人：
HONGMIN LI
金额：
$ 23.55万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9412543
关键词：
Acquired Immunodeficiency Syndrome Active Sites Address Adverse effects Affinity Animal Model Animals Antiviral Agents Arboviruses Area Arthropods Biological Assay Biological Availability Categories Cell Culture Techniques Cells Charge Cleaved cell Clinical Clinical Trials Complex Controlled Study Country Dengue Hemorrhagic Fever Dengue Vaccine Dengue Virus Development Disease Disease Outbreaks Dose Drug Kinetics Drug Targeting Emergency Situation Encephalitis Viruses Enzymes Essential Drugs FDA approved Family Fetus Flavivirus Flavivirus Infections Formulation Frequencies Goals Government Hepatitis C Histopathology Human In Vitro Infection Japanese Encephalitis Vaccines Japanese encephalitis virus Life Mass Vaccinations Meningitis Microcephaly Peptide Hydrolases Pharmaceutical Preparations Polyproteins Populations at Risk Pregnancy Pregnant Women Protease Inhibitor Protein Precursors Proteins Reproduction Risk Route Safety Therapeutic Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Time Vaccinated Vaccines Viral Viral Genome Viral Physiology Viral Proteins Viremia Virus Virus Assembly Virus Diseases Virus Replication West Nile Encephalitis West Nile virus Work World Health Organization Yellow fever virus Zika Virus burden of illness combat dosage drug candidate drug development efficacy study high throughput screening human disease improved in vivo inhibitor/antagonist innovation killings member mouse model nanoformulation nanoparticle nitazoxanide novel novel therapeutics pathogen public health emergency therapeutic target

项目摘要

Abstract: Majority of flaviviruses are significant human pathogens. Zika virus (ZIKV), a member of the flavivirus family, starts to emerge and causes severe human diseases. The World Health Organization (WHO) has declared ZIKV as a global public health emergency. There is currently neither effective vaccine nor specific therapy for ZIKV. For flaviviruses, a single viral polyprotein precursor is synthesized from the viral genome during infection of the host cell. The virus encodes its own protease, which works together with host proteases to cleave the protein precursor into its component proteins. The viral protease is composed of viral proteins NS2B and NS3. This viral protease is essential for virus assembly and replication. Using a high throughput screening assay, we identified several existing drugs, including niclosamide and nitazoxanide, that are potent and broad-spectrum flavivirus inhibitors. These drugs inhibited flavivirus protease via an orthosteric inhibition mechanism, by blocking the interactions between viral protease components NS2B and NS3. The major goal of this proposal is to perform reformulation, in vivo pharmacokinetics and efficacy studies to establish whether these two drugs, niclosamide and nitazoxanide, are effective in ZIKV animal model. These studies are essential for drug repurposing. The approval of new compounds as drugs by governmental drug administration agencies requires significant effort, time, and expense. If drugs that are already approved for treatment have additional capabilities that can be exploited therapeutically, repurposing them is the fastest route to develop new therapies.

摘要：大多数黄素病毒是重要的人类病原体。 Zika Virus（Zikv），成员 Flavivivirus家族开始出现并引起严重的人类疾病。世界健康组织（WHO）已宣布ZIKV为全球公共卫生紧急情况。目前有 ZIKV既不有效的疫苗或特定疗法。对于黄病毒，单个病毒多蛋白在宿主细胞感染期间，从病毒基因组合成前体。病毒编码它自己的蛋白酶，与宿主蛋白酶一起搭配，将蛋白质前体裂开其成分蛋白。病毒蛋白酶由病毒蛋白NS2B和NS3组成。这个病毒蛋白酶对于病毒组装和复制至关重要。使用高通量筛选测定法，我们确定了几种现有药物，包括烟酰胺和尼塔唑胺，它们是有效的，并且广谱黄素抑制剂。这些药物通过直角抑制黄素蛋白酶抑制机制，通过阻止病毒蛋白酶成分NS2B与 NS3。该提案的主要目标是进行重新制定，体内药代动力学和疗效研究确定这两种药物（烟酰胺和硝酸氮氧化物）是否有效在ZIKV动物模型中。这些研究对于重新利用药物至关重要。新的批准政府药物管理局作为药物的化合物需要大量努力，时间和费用。如果已经批准用于治疗的药物具有其他功能可以通过治疗剥削，重新利用它们是开发新的最快途径疗法。