Targeting Zika Virus Infection with Chloroquine and Related Drugs

项目摘要 寨卡病毒(Zika Virus，ZIKV)是最近被确认的全球公共卫生威胁，原因是寨卡病毒的广泛地理分布 先天性感染的风险和严重后果的可能性。迫切需要有效的 针对ZIKV的治疗策略已经确立了对人类的安全性，特别是在怀孕期间。我们的 初步数据显示，氯喹、羟氯喹和阿莫地喹可阻断ZIKV在体内的复制 在临床可达到的浓度下培养细胞。这些药物在中国已经使用了几十年 人类，包括怀孕期间。一类对寨卡病毒有效药物的鉴定 感染，耐受性好，怀孕期间安全，廉价，可广泛获得和口服生物利用度 可立即翻译的潜力，对这一持续流行的疫情产生重大影响。 这项建议旨在进一步发展体外模型，以研究氯喹及相关药物对血管紧张素转换酶的影响。 感染ZIKV，确定其活性的分子机制(S)并确定这些病原体 在小鼠模型中展示体内疗效。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，并确定保护是否发生在原代细胞 包括神经前体细胞和目前流行的ZIKV毒株。目标2将识别细胞和 氯喹及相关药物抑制作用的分子机制(S)。我们建议理解如何 这些药物工作将揭示对这种病毒的基本生物学的关键洞察力，以及服从于 治疗靶向。在目标3中，我们将测定氯喹及其相关化合物对小鼠的疗效。 ZIKV感染模型，这可能为支持人类临床试验提供临床前证据。 我们提议的实验不仅将确定氯喹和相关药物是否有效 对抗ZIKV，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有关，而且与当前医学上重要的相关黄病毒和 未来可能会出现的问题。

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.