Targeting Zika Virus Infection with Chloroquine and Related Drugs

用氯喹和相关药物治疗寨卡病毒感染

• 批准号: 9296242
• 负责人: Susan Leilani Fink
• 金额: $ 23.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296242
• 关键词: Amodiaquine; Animal Disease Models; Animal Model; Antimalarials; Autopsy; Binding; Bioavailable; Biology; Cells; Chloroquine; Clinical; Clinical Trials; Critical Pathways; Cultured Cells; Data; Dose; Endosomes; Environment; Epidemic; Flavivirus; Future; Geographic Distribution; Glycoproteins; Golgi Apparatus; Hela Cells; Human; Hydroxychloroquine; In Vitro; Infection prevention; Light; Link; Mediating; Medical; Microcephaly; Molecular; Oral; Pathway interactions; Pharmaceutical Preparations; Post-Translational Protein Processing; Pregnancy; Process; Public Health; Risk; Safety; Study models; Translating; Treatment Efficacy; Vaccines; Vero Cells; Viral; Virus; Virus Diseases; Virus Replication; Work; Zika Virus; adverse pregnancy outcome; base; cell type; clinical translation; congenital infection; drug development; effective therapy; epidemiologic data; experimental study; fetal; in vitro Model; in vivo; insight; mouse model; nerve stem cell; pre-clinical; preclinical efficacy; predicting response; response; therapeutic target; uptake

Project Summary Zika virus (ZIKV) is a recently recognized global public health threat due to the wide geographic distribution of risk and potential for severe consequences of congenital infection. There is an urgent need for effective therapeutic strategies against ZIKV that have established safety in humans, especially during pregnancy. Our preliminary data show that chloroquine, hydroxychloroquine and amodiaquine block ZIKV replication in cultured cells at clinically achievable concentrations. These medications have been used for many decades in humans, including during pregnancy. The identification of a class of drugs that are efficacious for ZIKV infection, well tolerated, safe in pregnancy, inexpensive, widely available and orally bioavailable would have the immediately translatable potential to significantly impact this ongoing epidemic. This proposal aims to further develop in vitro models to study the effect of chloroquine and related drugs on ZIKV infection, identify the molecular mechanism(s) of their activity and determine whether these agents demonstrate efficacy in vivo in mouse models. In Aim 1, we will perform dose-response experiments with chloroquine and a panel of related compounds and determine whether protection occurs in primary cells including neural progenitor cells and with currently circulating ZIKV strains. Aim 2 will identify the cellular and molecular mechanism(s) of inhibition by chloroquine and related drugs. We propose that understanding how these drugs work will reveal critical insights into the basic biology of this virus and pathways amenable to therapeutic targeting. In Aim 3, we will determine the efficacy of chloroquine and related compounds in mouse models of ZIKV infection, which may provide preclinical evidence to support clinical trials in humans. The experiments we propose will not only determine whether chloroquine and related drugs are efficacious against ZIKV, but also shed light on the basic biology of this virus, which will inform future drug development. Our findings may be relevant not only to ZIKV, but also related flaviviruses of current medical importance and ones that may emerge in the future.

项目摘要 寨卡病毒（ZIKV）是最近认识到的全球公共卫生威胁，由于其广泛的地理分布， 先天性感染的风险和潜在严重后果。迫切需要有效的 针对ZIKV的治疗策略已经在人类中建立了安全性，特别是在怀孕期间。我们 初步数据显示，氯喹、羟氯喹和阿莫地喹阻断ZIKV复制， 以临床可达到的浓度培养细胞。这些药物已经使用了几十年， 人类，包括怀孕期间。对ZIKV有效的一类药物的鉴定 感染，耐受性好，妊娠安全，价格便宜，广泛使用和口服生物利用度将 立即转化为对这一持续流行病产生重大影响的潜力。 这项建议旨在进一步发展体外模型，以研究氯喹和相关药物对 ZIKV感染，鉴定其活性的分子机制并确定这些试剂是否 在小鼠模型中显示出体内功效。在目标1中，我们将进行剂量反应实验， 氯喹和一组相关化合物，并确定是否在原代细胞中发生保护作用 包括神经祖细胞和目前流行的ZIKV毒株。目标2将识别细胞和 氯喹和相关药物抑制的分子机制。我们建议理解如何 这些药物的作用将揭示这种病毒的基本生物学和适合的途径的关键见解。 治疗靶向目的3：研究氯喹及其相关化合物对小鼠的药效 ZIKV感染的模型，其可以提供临床前证据以支持人类的临床试验。 我们提出的实验不仅将确定氯喹和相关药物是否有效 ZIKV病毒，但也揭示了这种病毒的基本生物学，这将为未来的药物开发提供信息。 我们的发现可能不仅与ZIKV相关，而且与当前医学重要性的相关黄病毒相关， 未来可能出现的问题。