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.

Public Health Relevance

There is an urgent need for effective therapeutic strategies against Zika virus that have established safety in humans, especially during pregnancy. Our preliminary data suggest that the anti-malarial drugs chloroquine, hydroxychloroquine and amodiaquine block Zika virus replication in cultured cells at clinically achievable concentrations. This proposal aims to further study the effect of chloroquine and related drugs on Zika virus infection, identify the molecular mechanism(s) of their activity and determine whether these agents are effective in mouse models of Zika virus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI130281-02
Application #
9559629
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Davis, Mindy I
Project Start
2017-09-06
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
den Hartigh, Andreas B; Fink, Susan L (2018) Pyroptosis Induction and Detection. Curr Protoc Immunol :e52
Fink, Susan L; Vojtech, Lucia; Wagoner, Jessica et al. (2018) The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep 8:8989
den Hartigh, Andreas B; Fink, Susan L (2018) Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages. J Vis Exp :