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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：大多数黄病毒是重要的人类病原体。寨卡病毒（ZIKV），成员黄病毒科的一种，开始出现并引起严重的人类疾病。世界卫生世界卫生组织（WHO）已宣布寨卡病毒为全球突发公共卫生事件。目前有既没有有效的疫苗，也没有针对 ZIKV 的特异性疗法。对于黄病毒，单一病毒多蛋白前体是在感染宿主细胞期间从病毒基因组合成的。该病毒编码它自己的蛋白酶，与宿主蛋白酶一起将蛋白质前体切割成其成分蛋白质。病毒蛋白酶由病毒蛋白NS2B和NS3组成。这个病毒式的蛋白酶对于病毒组装和复制至关重要。使用高通量筛选分析，我们确定了几种现有药物，包括氯硝柳胺和硝唑尼特，它们是有效且有效的广谱黄病毒抑制剂。这些药物通过正构抑制黄病毒蛋白酶抑制机制，通过阻断病毒蛋白酶成分 NS2B 和 NS3。该提案的主要目标是进行重新配制、体内药代动力学和功效研究以确定氯硝柳胺和硝唑尼特这两种药物是否有效在 ZIKV 动物模型中。这些研究对于药物的重新利用至关重要。新的批准政府药物管理机构将化合物作为药物需要付出巨大的努力，时间、费用。如果已经批准用于治疗的药物具有额外的功能可以在治疗上利用它们，重新利用它们是开发新药物的最快途径疗法。