Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus.
Animals
Antiviral Agents
/ pharmacology
Cell Line
Chikungunya virus
/ drug effects
Dengue Virus
/ drug effects
Encephalitis Virus, Japanese
/ drug effects
Gene Dosage
/ drug effects
Gene Expression
/ drug effects
Genome, Viral
/ drug effects
HEK293 Cells
Humans
Microbial Sensitivity Tests
Orlistat
/ pharmacology
Viral Proteins
/ genetics
Virus Replication
/ drug effects
Zika Virus
/ drug effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 01 2020
30 01 2020
Historique:
received:
27
10
2019
accepted:
15
01
2020
entrez:
1
2
2020
pubmed:
1
2
2020
medline:
18
11
2020
Statut:
epublish
Résumé
Many mosquito transmitted viruses of the genera Alphavirus and Flavivirus are human pathogens of significant concern, and there is currently no specific antiviral for any member of these two genera. This study sought to investigate the broad utility of orlistat (tetrahydrolipstatin) in reducing virus infection for several mosquito borne viruses including flaviviruses (dengue virus (DENV; nine isolates analyzed), Japanese encephalitis virus (JEV; one isolate analyzed) and Zika virus (ZIKV; 2 isolates analyzed)) as well as an alphavirus (chikungunya virus; CHIKV; 2 isolates analyzed). Three different treatment regimens were evaluated, namely pre-treatment (only), post-treatment (only) and pre- and post-treatment, and three factors were evaluated, namely level of infection, virus titer and genome copy number. Results showed that all three treatment modalities were able to significantly reduce virus titer for all viruses investigated, with the exception of three isolates of DENV in the pre-treatment only regimen. Pre- and post-treatment was more effective in reducing the level of infection and genome copy number of all viruses investigated than either pre-treatment or post-treatment alone. Collectively, these results suggest orlistat has potential as a broad-spectrum agent against multiple mosquito transmitted viruses.
Identifiants
pubmed: 32001767
doi: 10.1038/s41598-020-58468-8
pii: 10.1038/s41598-020-58468-8
pmc: PMC6992670
doi:
Substances chimiques
Antiviral Agents
0
Viral Proteins
0
Orlistat
95M8R751W8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1499Subventions
Organisme : Medical Research Council
ID : MR/R020566/1
Pays : United Kingdom
Références
Weaver, S. C. & Reisen, W. K. Present and future arboviral threats. Antivir. Res. 85, 328–345 (2010).
doi: 10.1016/j.antiviral.2009.10.008
King, A. M., Adams, M. J., Lefkowitz, E. J. & Carstens, E. B. Virus Taxonomy: IXth Report of the International Committee on Taxonomy of Viruses, vol 9. (San Diego, CA., 2012).
Smith, D. R. Waiting in the wings: The potential of mosquito transmitted flaviviruses to emerge. Crit. Rev. Microbiol. 43, 1–18 (2017).
doi: 10.1080/1040841X.2016.1230974
Schmaljohn, A. L. & McClain, D. In Medical Microbiology (ed. Baron, S.) (1996).
Baltimore, D. Expression of animal virus genomes. Bacteriol. Rev. 35, 235–241 (1971).
pubmed: 4329869
pmcid: 378387
Simmonds, P. et al. ICTV Virus Taxonomy Profile: Flaviviridae. J. Gen. Virol. 98, 2–3 (2017).
doi: 10.1099/jgv.0.000672
Chen, R. et al. ICTV Virus Taxonomy Profile: Togaviridae. J. Gen. Virol. (2018).
Campagnola, G., McDonald, S., Beaucourt, S., Vignuzzi, M. & Peersen, O. B. Structure-function relationships underlying the replication fidelity of viral RNA-dependent RNA polymerases. J. Virol. 89, 275–286 (2015).
doi: 10.1128/JVI.01574-14
Pulmanausahakul, R., Roytrakul, S., Auewarakul, P. & Smith, D. R. Chikungunya in Southeast Asia: understanding the emergence and finding solutions. Int. J. Infect. Dis. 15, 671–676 (2011).
doi: 10.1016/j.ijid.2011.06.002
Tsetsarkin, K. A., Vanlandingham, D. L., McGee, C. E. & Higgs, S. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 3, e201 (2007).
doi: 10.1371/journal.ppat.0030201
Wikan, N. & Smith, D. R. Zika virus: history of a newly emerging arbovirus. Lancet Infect. Dis. 16, E119–E126 (2016).
doi: 10.1016/S1473-3099(16)30010-X
Liu, Y. et al. Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes. Nature 545, 482–486 (2017).
doi: 10.1038/nature22365
Andrew, M. Q. K., Lefkowitz, E., Adams, M. J. & Carstens, E. B. Virus Taxonomy Classification and Nomenclature of Viruses. (2012).
Martin-Acebes, M. A., Vazquez-Calvo, A. & Saiz, J. C. Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses. Prog. Lipid Res. 64, 123–137 (2016).
doi: 10.1016/j.plipres.2016.09.005
Heaton, N. S. & Randall, G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 8, 422–432 (2010).
doi: 10.1016/j.chom.2010.10.006
Perera, R. et al. Dengue virus infection perturbs lipid homeostasis in infected mosquito cells. PLoS Pathog. 8, e1002584 (2012).
doi: 10.1371/journal.ppat.1002584
Samsa, M. M. et al. Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog. 5, e1000632 (2009).
doi: 10.1371/journal.ppat.1000632
Wakil, S. J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 28, 4523–4530 (1989).
doi: 10.1021/bi00437a001
Heck, A. M., Yanovski, J. A. & Calis, K. A. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy 20, 270–279 (2000).
doi: 10.1592/phco.20.4.270.34882
Rahman, M. T. et al. Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer. Oncology 84, 166–173 (2013).
doi: 10.1159/000342967
Flavin, R., Peluso, S., Nguyen, P. L. & Loda, M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 6, 551–562 (2010).
doi: 10.2217/fon.10.11
Wright, C., Iyer, A. K. V., Kaushik, V. & Azad, N. Anti-Tumorigenic Potential of a Novel Orlistat-AICAR Combination in Prostate Cancer Cells. J. Cell Biochem. 118, 3834–3845 (2017).
doi: 10.1002/jcb.26033
Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).
doi: 10.1158/0008-5472.CAN-03-3645
Menendez, J. A., Vellon, L. & Lupu, R. Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene. Ann. Oncol. 16, 1253–1267 (2005).
doi: 10.1093/annonc/mdi239
Chuang, H. Y., Chang, Y. F. & Hwang, J. J. Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed. Pharmacother. 65, 286–292 (2011).
doi: 10.1016/j.biopha.2011.02.016
Ammer, E. et al. The anti-obesity drug orlistat reveals anti-viral activity. Med. Microbiol. Immunol. 204, 635–645 (2015).
doi: 10.1007/s00430-015-0391-4
Tongluan, N. et al. Involvement of fatty acid synthase in dengue virus infection. Virology J. 14, 18 (2017).
doi: 10.1186/s12985-017-0685-9
Gubler, D. J. Dengue and dengue hemorrhagic fever. Clin. Microbiol. Rev. 11, 480–496 (1998).
doi: 10.1128/CMR.11.3.480
Pear, W. S., Nolan, G. P., Scott, M. L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl Acad. Sci. USA 90, 8392–8396 (1993).
doi: 10.1073/pnas.90.18.8392
Zhi, J., Melia, A. T., Eggers, H., Joly, R. & Patel, I. H. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J. Clin. Pharmacol. 35, 1103–1108 (1995).
doi: 10.1002/j.1552-4604.1995.tb04034.x
Zhi, J. et al. Metabolic profiles of minimally absorbed orlistat in obese/overweight volunteers. J. Clin. Pharmacol. 36, 1006–1011 (1996).
doi: 10.1177/009127009603601104
Wikan, N., Sakoonwatanyoo, P., Ubol, S., Yoksan, S. & Smith, D. R. Chikungunya virus infection of cell lines: analysis of the East, central and South african lineage. PLoS One 7, e31102 (2012).
doi: 10.1371/journal.pone.0031102
Henchal, E. A., Gentry, M. K., McCown, J. M. & Brandt, W. E. Dengue virus-specific and flavivirus group determinants identified with monoclonal antibodies by indirect immunofluorescence. Am. J. Trop. Med. Hyg. 31, 830–836 (1982).
doi: 10.4269/ajtmh.1982.31.830
Lanciotti, R. S., Calisher, C. H., Gubler, D. J., Chang, G. J. & Vorndam, A. V. Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction. J. Clin. Microbiol. 30, 545–551 (1992).
doi: 10.1128/JCM.30.3.545-551.1992
Rungruengphol, C. et al. Evidence of plasticity in the dengue virus: Host cell interaction. Microb. Pathog. 86, 18–25 (2015).
doi: 10.1016/j.micpath.2015.07.003
Collins, M. H. & Metz, S. W. Progress and Works in Progress: Update on Flavivirus Vaccine Development. Clin. Ther. 39, 1519–1536 (2017).
doi: 10.1016/j.clinthera.2017.07.001
Fatima, K. & Syed, N. I. Dengvaxia controversy: impact on vaccine hesitancy. J. Glob. Health 8, 010312 (2018).
doi: 10.7189/jogh.08.020312
Milligan, G. N. et al. Spectrum of activity testing for therapeutics against all four dengue virus serotypes in AG129 mouse models: Proof-of-concept studies with the adenosine nucleoside inhibitor NITD-008. Antivir. Res. 154, 104–109 (2018).
doi: 10.1016/j.antiviral.2018.04.012
Talarico, L. B. et al. The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. Antivir. Res. 66, 103–110 (2005).
doi: 10.1016/j.antiviral.2005.02.001
Vaughn, D. W. et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J. Infect. Dis. 181, 2–9 (2000).
doi: 10.1086/315215
Pemble, C. W. 4th, Johnson, L. C., Kridel, S. J. & Lowther, W. T. Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat. Nat. Struct. Mol. Biol. 14, 704–709 (2007).
Schcolnik-Cabrera, A. et al. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expert. Opin. Investig. Drugs 27, 475–489 (2018).
doi: 10.1080/13543784.2018.1471132
Buckley, D. et al. Fatty acid synthase - Modern tumor cell biology insights into a classical oncology target. Pharmacol. Ther. 177, 23–31 (2017).
doi: 10.1016/j.pharmthera.2017.02.021
Chang, J. et al. Combination of alpha-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antivir. Res. 89, 26–34 (2011).
doi: 10.1016/j.antiviral.2010.11.002
Whitby, K. et al. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J. Virol. 79, 8698–8706 (2005).
doi: 10.1128/JVI.79.14.8698-8706.2005