ZIKA virus assembly inhibitors

ZIKA 病毒组装抑制剂

• 批准号: 9392394
• 负责人: FENG LI
• 金额: $ 17.92万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392394
• 关键词: Alpha Cell; Americas; Antiviral Agents; Attributes of Chemicals; Biological Assay; Biology; Boston; Capsid; Capsid Proteins; Cells; Chemicals; Clinical; Collection; Complement; Complex; Country; Culicidae; Data; Dengue; Dengue Virus; Development; Dimerization; Enzymes; Family; Fetus; Flavivirus; Foundations; France; Future; Genome; Goals; Human; Infection; Japanese Encephalitis; Lead; Letters; Luciferases; Measures; Membrane; Microcephaly; Mothers; Permeability; Pharmaceutical Chemistry; Proteins; Public Health; Publishing; Reproducibility; Research; Research Proposals; Role; Signal Transduction; Specificity; System; Vaccines; Validation; Viral; Viral Genome; Viral Proteins; Virion; Virus; Virus Assembly; Virus Diseases; Virus Replication; West Nile virus; Work; Zika Virus; assay development; base; combat; dimer; drug candidate; drug discovery; global health; high throughput screening; inhibitor/antagonist; insight; luminescence; medical schools; member; multidisciplinary; novel; pandemic disease; pregnant; protein protein interaction; screening; small molecule inhibitor; small molecule libraries; stable cell line; tool; viral RNA

Abstract Since its introduction, in May 2015, the mosquito-borne Zika virus (ZIKV) has rapidly spread to more than 40 countries throughout the South Pacific and the Americas. The association between infection with ZIKV while pregnant and the occurrence of microcephaly in the fetus has raised a significant public health concern. To date, there is no effective antiviral treatment or vaccine to combat this rapidly escalating pandemic. The primary focus of this R21 application is to develop a novel Zika virus (ZIKV) capsid-capsid interaction assay and employ it to screen and identify chemical inhibitors of ZIKV replication. The formation of the ZIKV capsid protein dimer is a prerequisite to executing multiple functions in the virus lifecycle. Previous studies on other ZIKV-related C proteins have provided ample evidence that a relatively subtle perturbation in the efficiency and timing of C protein dimerization can disrupt proper viral assembly/disassembly and block virus infectivity. A recently described Dengue virus capsid assembly inhibitor supports the feasibility of our approach in exploring the ZIKV capsid as a target for anti-ZIKV drug discovery. Successful completion of this project will allow us develop a novel high-throughput assay for identifying ZIKV capsid assembly/disassembly inhibitors. The compounds identified through this work can be further studied to develop viable anti-ZIKV drug candidates that could be used for treatment of ZIKV infection in humans.

摘要 自2015年5月引入以来，蚊媒寨卡病毒（ZIKV）迅速传播到更多 南太平洋和美洲的40多个国家。感染与 ZIKV在怀孕期间和胎儿小头畸形的发生引起了重大的公共卫生问题 关心到目前为止，还没有有效的抗病毒治疗或疫苗来对抗这种迅速升级的疾病。 流行病 这项R21申请的主要重点是开发一种新型寨卡病毒（ZIKV）衣壳-衣壳蛋白。 相互作用测定并将其用于筛选和鉴定ZIKV复制的化学抑制剂。形成 ZIKV衣壳蛋白二聚体的蛋白质重链是在病毒生命周期中执行多种功能的先决条件。 先前对其他ZIKV相关C蛋白的研究提供了充分的证据，表明一种相对微妙的 C蛋白二聚化的效率和时间的扰动可以破坏适当的病毒 组装/拆卸和阻断病毒传染性。一种新近发现的登革病毒衣壳装配抑制剂 支持我们的方法在探索ZIKV衣壳作为抗ZIKV药物发现的靶标中的可行性。 该项目的成功完成将使我们能够开发一种新的高通量检测方法， 鉴定ZIKV衣壳组装/分解抑制剂。通过这项工作鉴定的化合物可以 进一步研究以开发可用于治疗ZIKV感染的可行的抗ZIKV候选药物 在人类身上。