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

基本信息

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
项目类别：
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

项目摘要

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）是最近公认的全球公共卫生威胁，因为先天性感染严重后果的风险和潜力。迫切需要有效针对ZIKV的治疗策略已经在人类中建立了安全性，尤其是在怀孕期间。我们的初步数据表明，氯喹，羟基氯喹和amodiaquine Block zikv复制在临床上可实现的浓度下培养的细胞。这些药物已经使用了数十年人类，包括怀孕期间。识别有效ZIKV的一类药物感染，耐受性良好，在怀孕中安全，廉价，广泛可用和口服生物利用立即翻译的潜力，以显着影响这种持续的流行病。该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，确定其活性的分子机制，并确定这些药物是否是否在小鼠模型中证明体内功效。在AIM 1中，我们将对氯喹和一组相关化合物，并确定在原代细胞中是否发生保护包括神经祖细胞以及目前循环的ZIKV菌株。 AIM 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工作将揭示有关该病毒的基本生物学的关键见解，并可以治疗靶向。在AIM 3中，我们将确定小鼠氯喹和相关化合物的功效 ZIKV感染的模型，该模型可能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反对ZIKV，但也阐明了该病毒的基本生物学，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，而且还与当前医学重要性相关的黄病毒和将来可能会出现的。