Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines, Viruses, and Compounds
2.2. Drug Inhibition Assay
2.3. Immunofluorescence (IF) Assay
2.4. Cell Viability Assay
2.5. Real-Time Quantitative PCR (RT-qPCR)
2.6. Viral Kinetics Assay
2.7. Time-of-Drug-Addition Assay
2.8. Binding Assay
2.9. Endocytosis Assay
2.10. Transferrin Uptake Assay
2.11. Membrane Fusion Assay
2.12. Genome Transfection Assay
2.13. Replicon Expression Assay
2.14. In Vivo Experiment
2.15. Statistical Analysis
3. Results
3.1. Nifuroxazide Dose-Dependently Inhibits CHIKV Infection in Huh7 Cells and HUVECs but Not in SY5Y Cells
3.2. The Antiviral Efficacy of Nifuroxazide in Other Arboviruses
3.3. Nifuroxazide Shows Minor Effects on the Entry Process of CHIKV
3.4. Nifuroxazide Suppressed CHIKV Replication but Not Assembly and Release
3.5. Nifuroxazide Protects Mice from CHIKV-Induced Severe Disease
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Suhrbier, A. Rheumatic manifestations of chikungunya: Emerging concepts and interventions. Nat. Rev. Rheumatol. 2019, 15, 597–611. [Google Scholar] [CrossRef]
- Cassadou, S.; Boucau, S.; Petit-Sinturel, M.; Huc, P.; Leparc-Goffart, I.; Ledrans, M. Emergence of chikungunya fever on the French side of Saint Martin island, October to December 2013. Eurosurveillance 2014, 19, 20752. [Google Scholar] [CrossRef]
- Zeller, H.; Van Bortel, W.; Sudre, B. Chikungunya: Its history in Africa and Asia and its spread to new regions in 2013–2014. J. Infect. Dis. 2016, 214, S436–S440. [Google Scholar] [CrossRef]
- Burt, F.J.; Chen, W.; Miner, J.J.; Lenschow, D.J.; Merits, A.; Schnettler, E.; Kohl, A.; Rudd, P.A.; Taylor, A.; Herrero, L.J.; et al. Chikungunya virus: An update on the biology and pathogenesis of this emerging pathogen. Lancet Infect. Dis. 2017, 17, e107–e117. [Google Scholar] [CrossRef]
- Mbaika, S.; Lutomiah, J.; Chepkorir, E.; Mulwa, F.; Khayeka-Wandabwa, C.; Tigoi, C.; Oyoo-Okoth, E.; Mutisya, J.; Ng’ang’a, Z.; Sang, R. Vector competence of Aedes aegypti in transmitting Chikungunya virus: Effects and implications of extrinsic incubation temperature on dissemination and infection rates. Virol. J. 2016, 13, 114. [Google Scholar] [CrossRef] [PubMed]
- Young, A.R.; Locke, M.C.; Cook, L.E.; Hiller, B.E.; Zhang, R.; Hedberg, M.L.; Monte, K.J.; Veis, D.J.; Diamond, M.S.; Lenschow, D.J. Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA. PLoS Pathog. 2019, 15, e1007993. [Google Scholar] [CrossRef]
- Paul, B.J.; Sadanand, S. Chikungunya Infection: A re-emerging epidemic. Rheumatol. Ther. 2018, 5, 317–326. [Google Scholar] [CrossRef] [PubMed]
- Mehta, R.; Gerardin, P.; de Brito, C.A.A.; Soares, C.N.; Ferreira, M.L.B.; Solomon, T. The neurological complications of chikungunya virus: A systematic review. Rev. Med. Virol. 2018, 28, e1978. [Google Scholar] [CrossRef] [PubMed]
- Cai, L.; Hu, X.; Liu, S.; Wang, L.; Lu, H.; Tu, H.; Huang, X.; Tong, Y. The research progress of Chikungunya fever. Front. Public Health 2023, 10, 1095549. [Google Scholar] [CrossRef] [PubMed]
- Gérardin, P.; Couderc, T.; Bintner, M.; Tournebize, P.; Renouil, M.; Lémant, J.; Boisson, V.; Borgherini, G.; Staikowsky, F.; Schramm, F.; et al. Chikungunya virus-associated encephalitis: A cohort study on La Réunion Island, 2005–2009. Neurology 2016, 86, 94–102. [Google Scholar] [CrossRef]
- Gérardin, P.; Sampériz, S.; Ramful, D.; Boumahni, B.; Bintner, M.; Alessandri, J.L.; Carbonnier, M.; Tiran-Rajaoefera, I.; Beullier, G.; Boya, I.; et al. Neurocognitive outcome of children exposed to perinatal mother-to-child Chikungunya virus infection: The CHIMERE cohort study on Reunion Island. PLoS Negl. Trop. Dis. 2014, 8, e2996. [Google Scholar] [CrossRef] [PubMed]
- Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019, 18, 41–58. [Google Scholar] [CrossRef] [PubMed]
- Trivedi, J.; Mohan, M.; Byrareddy, S.N. Drug repurposing approaches to combating viral infections. J. Clin. Med. 2020, 9, 3777. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Peng, T. Strategy, progress, and challenges of drug repurposing for efficient antiviral discovery. Front. Pharmacol. 2021, 12, 660710. [Google Scholar] [CrossRef] [PubMed]
- Zeng, S.; Meng, X.; Huang, Q.; Lei, N.; Zeng, L.; Jiang, X.; Guo, X. Spiramycin and azithromycin, safe for administration to children, exert antiviral activity against enterovirus A71 in vitro and in vivo. Int. J. Antimicrob. Agents. 2019, 53, 362–369. [Google Scholar] [CrossRef] [PubMed]
- Trukhacheva, L.A.; Grigor’ev, N.B.; Arzamastsev, A.P. Hydrolytic and reductive transformations of nifuroxazide. Pharm. Chem. J. 2005, 39, 381–384. [Google Scholar] [CrossRef]
- Lago, E.M.; Xavier, R.P.; Teixeira, T.R.; Silva, L.M.; da Silva Filho, A.A.; de Moraes, J. Antischistosomal agents: State of art and perspectives. Future Med. Chem. 2018, 10, 89–120. [Google Scholar] [CrossRef] [PubMed]
- Jiao, F.; Andrianov, A.M.; Wang, L.; Furs, K.V.; Gonchar, A.V.; Wang, Q.; Xu, W.; Lu, L.; Xia, S.; Tuzikov, A.V.; et al. Repurposing Navitoclax to block SARS-CoV-2 fusion and entry by targeting heptapeptide repeat sequence 1 in S2 protein. J. Med. Virol. 2023, 95, e29145. [Google Scholar] [CrossRef]
- Catalano, A.; Iacopetta, D.; Pellegrino, M.; Aquaro, S.; Franchini, C.; Sinicropi, M.S. Diarylureas: Repositioning from antitumor to antimicrobials or multi-target agents against new pandemics. Antibiotics 2021, 10, 92. [Google Scholar] [CrossRef]
- Ding, C.; Tang, W.; Xia, B.; Peng, H.; Liu, Y.; Wang, J.; Zheng, X.; Liu, Y.; Zhao, L.; He, Y.; et al. High-throughput screening of FDA-approved drug library reveals ixazomib is a broad-spectrum antiviral agent against arboviruses. Viruses 2022, 14, 1381. [Google Scholar] [CrossRef]
- Qian, X.; Wu, B.; Tang, H.; Luo, Z.; Xu, Z.; Ouyang, S.; Li, X.; Xie, J.; Yi, Z.; Leng, Q.; et al. Rifapentine is an entry and replication inhibitor against yellow fever virus both in vitro and in vivo. Emerg. Microbes Infect. 2022, 11, 873–884. [Google Scholar] [CrossRef]
- He, Y.; Pan, Z.; Liu, Y.; Jiang, L.; Peng, H.; Zhao, P.; Qi, Z.; Liu, Y.; Tang, H. Identification of tyrphostin AG879 and A9 inhibiting replication of Chikungunya virus by screening of a kinase inhibitor library. Virology 2023, 588, 109900. [Google Scholar] [CrossRef]
- Liu, Y.G.; Chen, Y.; Wang, X.; Zhao, P.; Zhu, Y.; Qi, Z. Ezrin is essential for the entry of Japanese encephalitis virus into the human brain microvascular endothelial cells. Emerg. Microbes Infect. 2020, 9, 1330–1341. [Google Scholar] [CrossRef] [PubMed]
- Bagchi, P.; Speckhart, K.; Kennedy, A.; Tai, A.W.; Tsai, B. A specific EMC subunit supports Dengue virus infection by promoting virus membrane fusion essential for cytosolic genome delivery. PLoS Pathog. 2022, 18, e1010717. [Google Scholar] [CrossRef]
- Zhu, Y.; Ye, T.; Yu, X.; Lei, Q.; Yang, F.; Xia, Y.; Song, X.; Liu, L.; Deng, H.; Gao, T.; et al. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma. Sci. Rep. 2016, 6, 20253. [Google Scholar] [CrossRef] [PubMed]
- Tang, W.D.; Tang, H.L.; Peng, H.R.; Ren, R.W.; Zhao, P.; Zhao, L.J. Inhibition of tick-borne encephalitis virus in cell cultures by ribavirin. Front. Microbiol. 2023, 14, 1182798. [Google Scholar] [CrossRef]
- Holmes, A.C.; Basore, K.; Fremont, D.H.; Diamond, M.S. A molecular understanding of alphavirus entry. PLoS Pathog. 2020, 16, e1008876. [Google Scholar] [CrossRef]
- Dodge, M.J.; MacNeil, K.M.; Tessier, T.M.; Weinberg, J.B.; Mymryk, J.S. Emerging antiviral therapeutics for human adenovirus infection: Recent developments and novel strategies. Antivir. Res. 2021, 188, 105034. [Google Scholar] [CrossRef] [PubMed]
- Rodenhuis-Zybert, I.A.; Wilschut, J.; Smit, J.M. Dengue virus life cycle: Viral and host factors modulating infectivity. Cell Mol. Life Sci. 2010, 67, 2773–2786. [Google Scholar] [CrossRef] [PubMed]
- Wu, P.; Yu, X.; Wang, P.; Cheng, G. Arbovirus lifecycle in mosquito: Acquisition, propagation and transmission. Expert Rev. Mol. Med. 2019, 21, e1. [Google Scholar] [CrossRef]
- Tian, L.; Qiang, T.; Liang, C.; Ren, X.; Jia, M.; Zhang, J.; Li, J.; Wan, M.; YuWen, X.; Li, H.; et al. RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic. Eur. J. Med. Chem. 2021, 213, 113201. [Google Scholar] [CrossRef] [PubMed]
- Roquini, V.; Mengarda, A.C.; Cajas, R.A.; Martins-da-Silva, M.F.; Godoy-Silva, J.; Santos, G.A.; Espírito-Santo, M.C.C.; Pavani, T.F.A.; Melo, V.A.; Salvadori, M.C.; et al. The existing drug nifuroxazide as an antischistosomal agent: In vitro, in vivo, and in silico studies of macromolecular targets. Microbiol. Spectr. 2023, 11, e0139323. [Google Scholar] [CrossRef]
- Simon, F.; Caumes, E.; Jelinek, T.; Lopez-Velez, R.; Steffen, R.; Chen, L.H. Chikungunya: Risks for travellers. J. Travel. Med. 2023, 30, taad008. [Google Scholar] [CrossRef]
- Gardner, C.L.; Ryman, K.D. Yellow fever: A reemerging threat. Clin. Lab. Med. 2010, 30, 237–260. [Google Scholar] [CrossRef]
- Centers for Disease Control and Prevention (CDC). West Nile Virus Disease Cases and Deaths Reported to CDC by Year and Clinical Presentation, 1999–2023. Available online: https://www.cdc.gov/west-nile-virus/data-maps/index.html (accessed on 18 June 2024).
- Haussig, J.M.; Young, J.J.; Gossner, C.M.; Mezei, E.; Bella, A.; Sirbu, A.; Pervanidou, D.; Drakulovic, M.B.; Sudre, B. Early start of the West Nile fever transmission season 2018 in Europe. Eurosurveillance 2018, 23, 1800428. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Shi, W.; Wang, X.; Lu, J.J.; He, P.; Zhang, H.; Chen, X. Nifuroxazide boosts the anticancer efficacy of palbociclib-induced senescence by dual inhibition of STAT3 and CDK2 in triple-negative breast cancer. Cell Death Discov. 2023, 9, 355. [Google Scholar] [CrossRef] [PubMed]
- Li, D.; Liu, L.; Li, F.; Ma, C.; Ge, K. Nifuroxazide induces the apoptosis of human non-small cell lung cancer cells through the endoplasmic reticulum stress PERK signaling pathway. Oncol. Lett. 2023, 25, 248. [Google Scholar] [CrossRef]
- Sarvi, S.; Crispin, R.; Lu, Y.; Zeng, L.; Hurley, T.D.; Houston, D.R.; von Kriegsheim, A.; Chen, C.H.; Mochly-Rosen, D.; Ranzani, M.; et al. ALDH1 bio-activates nifuroxazide to eradicate ALDH high melanoma-initiating cells. Cell Chem. Biol. 2018, 25, 1456–1469. [Google Scholar] [CrossRef]
- Ren, H.; Wang, J.; Tang, H.; Qian, X.; Xia Bv Luo, Z.; Xu, Z.; Qi, Z.; Zhao, P. Tiratricol inhibits yellow fever virus replication through targeting viral RNA-dependent RNA polymerase of NS5. Antivir. Res. 2023, 219, 105737. [Google Scholar] [CrossRef]
- Zhang, H.L.; Dong, H.L.; Zhang, Y.N.; Xu, L.L.; Deng, C.L.; Li, X.F.; Li, X.D.; Ye, H.Q.; Yuan, Z.M.; Qin, C.F.; et al. Visualization of chikungunya virus infection in vitro and in vivo. Emerg. Microbes Infect. 2019, 8, 1574–1583. [Google Scholar] [CrossRef]
- Khodir, A.E.; Samra, Y.A.; Said, E. A novel role of nifuroxazide in attenuation of sepsis-associated acute lung and myocardial injuries; role of TLR4/NLPR3/IL-1β signaling interruption. Life Sci. 2020, 256, 117907. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Liu, Y.; Xu, M.; Xia, B.; Qiao, Z.; He, Y.; Liu, Y.; Pan, Z.; Zhang, C.; Peng, H.; Liang, X.; et al. Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication. Viruses 2024, 16, 1322. https://doi.org/10.3390/v16081322
Liu Y, Xu M, Xia B, Qiao Z, He Y, Liu Y, Pan Z, Zhang C, Peng H, Liang X, et al. Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication. Viruses. 2024; 16(8):1322. https://doi.org/10.3390/v16081322
Chicago/Turabian StyleLiu, Yangang, Mingxiao Xu, Binghui Xia, Zhuoyue Qiao, Yanhua He, Yan Liu, Zhendong Pan, Congcong Zhang, Haoran Peng, Xuesong Liang, and et al. 2024. "Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication" Viruses 16, no. 8: 1322. https://doi.org/10.3390/v16081322