The ubiquitin-proteasome system is essential for the productive entry of Japanese encephalitis virus

Wang, Shaobo; Liu, Haibin; Zu, Xiangyang; Liu, Yang; Chen, Liman; Zhu, Xueqiong; Zhang, Leike; Zhou, Zheng; Xiao, Gengfu; Wang, Wei

doi:10.1016/j.virol.2016.08.013

Cited by 44 publications

(41 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous quantitative proteomic analysis found that multiple host proteins involved in the UPS were regulated in JEV-infected cells, and further functional study indicated that RanBP2, an E3 ligase, can affect JEV replication (11). Our recent work found that the UPS plays an important role in the JEV entry process (55).…”

Section: Discussionmentioning

confidence: 90%

Quantitative Proteomic Analysis of Mosquito C6/36 Cells Reveals Host Proteins Involved in Zika Virus Infection

Xin

Deng

Chen

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

Zika virus (ZIKV) is an emerging arbovirus belonging to the genus of the family During replication processes, flavivirus manipulates host cell systems to facilitate its replication, while the host cells activate antiviral responses. Identification of host proteins involved in the flavivirus replication process may lead to the discovery of antiviral targets. The mosquitoes and are epidemiologically important vectors for ZIKV, and effective restrictions of ZIKV replication in mosquitoes will be vital in controlling the spread of virus. In this study, an iTRAQ-based quantitative proteomic analysis of ZIKV-infected C6/36 cells was performed to investigate host proteins involved in the ZIKV infection process. A total of 3,544 host proteins were quantified, with 200 being differentially regulated, among which CHCHD2 can be upregulated by ZIKV infection in both mosquito C6/36 and human HeLa cells. Our further study indicated that CHCHD2 can promote ZIKV replication and inhibit beta interferon (IFN-β) production in HeLa cells, suggesting that ZIKV infection may upregulate CHCHD2 to inhibit IFN-I production and thus promote virus replication. Bioinformatics analysis of regulated host proteins highlighted several ZIKV infection-regulated biological processes. Further study indicated that the ubiquitin proteasome system (UPS) plays roles in the ZIKV entry process and that an FDA-approved inhibitor of the 20S proteasome, bortezomib, can inhibit ZIKV infection Our study illustrated how host cells respond to ZIKV infection and also provided a candidate drug for the control of ZIKV infection in mosquitoes and treatment of ZIKV infection in patients. ZIKV infection poses great threats to human health, and there is no FDA-approved drug available for the treatment of ZIKV infection. During replication, ZIKV manipulates host cell systems to facilitate its replication, while host cells activate antiviral responses. Identification of host proteins involved in the ZIKV replication process may lead to the discovery of antiviral targets. In this study, the first quantitative proteomic analysis of ZIKV-infected cells was performed to investigate host proteins involved in the ZIKV replication process. Bioinformatics analysis highlighted several ZIKV infection-regulated biological processes. Further study indicated that the ubiquitin proteasome system (UPS) plays roles in the ZIKV entry process and that an FDA-approved inhibitor of the UPS, bortezomib, can inhibit ZIKV infection Our study not only illustrated how host cells respond to ZIKV infection but also provided a candidate drug for the control of ZIKV infection in mosquitoes and treatment of ZIKV infection in patients.

show abstract

Section: Discussionmentioning

confidence: 90%

Quantitative Proteomic Analysis of Mosquito C6/36 Cells Reveals Host Proteins Involved in Zika Virus Infection

Xin

Deng

Chen

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Screening of an FDA-approved drug library for inhibitors of JEV infection. Recombinant viral particles (RVPs) with the luciferase-reporting replicon enveloped by the JEV structural proteins were used to select inhibitors, with a focus on those that inhibit virus entry and replication, by a high-throughput screening (HTS) assay (4,5). The number of genomic RNA copies of RVP was determined to be 8.4 ϫ 10 6 copies/ml by using a standard curve generated with plasmids carrying the infectious clone.…”

Section: Resultsmentioning

confidence: 99%

“…JEV strain AT31, the WNV replicon, and the DENV-2 replicon expressing Renilla luciferase (Rluc) were kindly provided by Bo Zhang, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), China. JEV replicon recombinant viral particles (RVPs) were generated as previously described (4,5). ZIKV strain H/PF/2013, kindly provided by the European Virus Archive Goes Global, was propagated and titrated in Vero cells.…”

Section: Methodsmentioning

confidence: 99%

Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection

Wang

Liu

Guo

et al. 2017

J Virol

Self Cite

116

View full text Add to dashboard Cite

Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.

show abstract

“…By using this efficient approach the authors identified 286 genes which are involved in mechanism of JEV infection [216]. Based on in vivo studies in mice model, it is observed that bortezomib, an anticancer drug indicated for multiple myeloma and lymphoma can lower JEV-induced death in mice, along with alleviating the suffering in JEV infection and also reduce the brain damage possibly by proteasome inhibition [217,218]. This study highlights the possibility of a new drug candidate for JEV treatment.…”

Section: Drug Repurposing For Infectious Diseasesmentioning

confidence: 96%

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work

Kumar

Harilal

Gupta

et al. 2019

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

a b s t r a c tDrug discovery and development are long and financially taxing processes. On an average it takes 12e15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.

show abstract

The ubiquitin-proteasome system is essential for the productive entry of Japanese encephalitis virus

Cited by 44 publications

References 60 publications

Quantitative Proteomic Analysis of Mosquito C6/36 Cells Reveals Host Proteins Involved in Zika Virus Infection

Quantitative Proteomic Analysis of Mosquito C6/36 Cells Reveals Host Proteins Involved in Zika Virus Infection

Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work

Contact Info

Product

Resources

About