Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL
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Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL. / Pan, Ting; Peng, Zhilin; Tan, Likai; Zou, Fan; Zhou, Nan; Liu, Bingfeng; Liang, Liting; Chen, Cancan; Liu, Jun; Wu, Liyang; Liu, Guangyan; Peng, Zhiqin; Liu, Weiwei; Ma, Xiancai; Zhang, Junsong; Zhu, Xun; Liu, Ting; Li, Mengfeng; Huang, Xi; Tao, Liang; Zhang, Yiwen; Zhang, Hui.
in: J VIROL, Jahrgang 92, Nr. 20, 15.10.2018.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL
AU - Pan, Ting
AU - Peng, Zhilin
AU - Tan, Likai
AU - Zou, Fan
AU - Zhou, Nan
AU - Liu, Bingfeng
AU - Liang, Liting
AU - Chen, Cancan
AU - Liu, Jun
AU - Wu, Liyang
AU - Liu, Guangyan
AU - Peng, Zhiqin
AU - Liu, Weiwei
AU - Ma, Xiancai
AU - Zhang, Junsong
AU - Zhu, Xun
AU - Liu, Ting
AU - Li, Mengfeng
AU - Huang, Xi
AU - Tao, Liang
AU - Zhang, Yiwen
AU - Zhang, Hui
N1 - Copyright © 2018 American Society for Microbiology.
PY - 2018/10/15
Y1 - 2018/10/15
N2 - Zika virus (ZIKV) is genetically and biologically related to other Flaviviridae family members and has disseminated to many countries. It is associated with severe consequences, including the abnormal development of the neural system in fetuses and neurological diseases in adults. Therefore, the development of anti-ZIKV drugs is of paramount importance. Screening of generic drugs revealed that several nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, naproxen, acetaminophen, and lornoxicam, potently inhibited the entry of Zika virus Env/HIV-1-pseudotyped viruses. They also significantly inhibited the replication of wild-type ZIKV both in cell lines and in primary human fetal endothelial cells. Interestingly, the NSAIDs exerted this inhibitory effect by potently reducing the expression of AXL, the entry cofactor of ZIKV. Further studies showed that the NSAIDs downregulated the prostaglandin E2/prostaglandin E receptor 2 (EP2)/cAMP/protein kinase A (PKA) signaling pathway and reduced PKA-dependent CDC37 phosphorylation and the interaction between CDC37 and HSP90, which subsequently facilitated CHIP/ubiquitination/proteasome-mediated AXL degradation. Taken together, our results highlight a new mechanism of action of antiviral agents which may assist in designing a convenient strategy for treating ZIKV-infected patients.IMPORTANCE Zika virus (ZIKV) infection, which causes congenital malformations, including microcephaly and other neurological disorders, has attracted global attention. We observed that several NSAIDs significantly inhibited ZIKV infection. Based on our observations, we propose a novel mechanism of action of antiviral compounds which involves the blockade of virus entry via degradation of the entry cofactor. Furthermore, NSAIDs can be practically used for preventing ZIKV infection in pregnant women, as certain NSAIDs, including ibuprofen and acetaminophen, are considered clinically safe.
AB - Zika virus (ZIKV) is genetically and biologically related to other Flaviviridae family members and has disseminated to many countries. It is associated with severe consequences, including the abnormal development of the neural system in fetuses and neurological diseases in adults. Therefore, the development of anti-ZIKV drugs is of paramount importance. Screening of generic drugs revealed that several nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, naproxen, acetaminophen, and lornoxicam, potently inhibited the entry of Zika virus Env/HIV-1-pseudotyped viruses. They also significantly inhibited the replication of wild-type ZIKV both in cell lines and in primary human fetal endothelial cells. Interestingly, the NSAIDs exerted this inhibitory effect by potently reducing the expression of AXL, the entry cofactor of ZIKV. Further studies showed that the NSAIDs downregulated the prostaglandin E2/prostaglandin E receptor 2 (EP2)/cAMP/protein kinase A (PKA) signaling pathway and reduced PKA-dependent CDC37 phosphorylation and the interaction between CDC37 and HSP90, which subsequently facilitated CHIP/ubiquitination/proteasome-mediated AXL degradation. Taken together, our results highlight a new mechanism of action of antiviral agents which may assist in designing a convenient strategy for treating ZIKV-infected patients.IMPORTANCE Zika virus (ZIKV) infection, which causes congenital malformations, including microcephaly and other neurological disorders, has attracted global attention. We observed that several NSAIDs significantly inhibited ZIKV infection. Based on our observations, we propose a novel mechanism of action of antiviral compounds which involves the blockade of virus entry via degradation of the entry cofactor. Furthermore, NSAIDs can be practically used for preventing ZIKV infection in pregnant women, as certain NSAIDs, including ibuprofen and acetaminophen, are considered clinically safe.
KW - A549 Cells
KW - Animals
KW - Anti-Inflammatory Agents, Non-Steroidal/pharmacology
KW - Cell Line
KW - Chlorocebus aethiops
KW - Down-Regulation
KW - Endothelial Cells/cytology
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Mice
KW - Proteolysis
KW - Proto-Oncogene Proteins/metabolism
KW - Receptor Protein-Tyrosine Kinases/metabolism
KW - Vero Cells
KW - Virus Internalization/drug effects
KW - Virus Replication/drug effects
KW - Zika Virus/drug effects
KW - Zika Virus Infection/virology
U2 - 10.1128/JVI.01018-18
DO - 10.1128/JVI.01018-18
M3 - SCORING: Journal article
C2 - 30068645
VL - 92
JO - J VIROL
JF - J VIROL
SN - 0022-538X
IS - 20
ER -
