Antiviral Effect and Mechanism of Phillyrin and Its Reformulated FS21 Against Influenza

Overview

Journal Influenza Other Respir Viruses

Publisher Wiley

Specialty Microbiology

Date 2023 Mar 6

PMID 36875207

Authors

Yan Chen

Cunjin Wu

Huifen Li

Harrison Powell

Allison Chen

Guodong Zhu

Weihong Cong

Li Fu

Andrew Pekosz

Sean X Leng

Affiliations

Soon will be listed here.

Abstract

Background: Influenza virus causes significant morbidity and mortality with pandemic threat. is a medicinal herb. This study aimed to investigate antiviral effect of Phillyrin, a purified bioactive compound from this herb, and its reformulated preparation FS21 against influenza and its mechanism.

Methods: Madin-Darby Canine Kidney (MDCK) cells were infected by one of six influenza viruses: five influenza A viruses (IAVs: three H1N1 and two H3N2) and one influenza B virus (IBV). Virus-induced cytopathic effects were observed and recorded under microscope. Viral replication and mRNA transcription were evaluated by quantitative polymerase chain reaction (qPCR) and protein expression by Western blot. Infectious virus production was assessed using TCID50 assay, and IC50 was calculated accordingly. Pretreatment and time-of-addition experiments with Phillyrin or FS21 added 1 h before or in early (0-3 h), mid (3-6 h), or late (6-9 h) stages of viral infection were performed to assess their antiviral effects. Mechanistic studies included hemagglutination and neuraminidase inhibition, viral binding and entry, endosomal acidification, and plasmid-based influenza RNA polymerase activity.

Results: Phillyrin and FS21 had potent antiviral effects against all six IAV and IBV in a dose-dependent manner. Mechanistic studies showed that both suppressed influenza viral RNA polymerase with no effect on virus-mediated hemagglutination inhibition, viral binding or entry, endosomal acidification, or neuraminidase activity.

Conclusions: Phillyrin and FS21 have broad and potent antiviral effects against influenza viruses with inhibition of viral RNA polymerase as the distinct antiviral mechanism.

Citing Articles

Phillyrin ameliorates influenza a virus-induced pulmonary inflammation by antagonizing CXCR2 and inhibiting NLRP3 inflammasome activation.

Zhang S, Sun F, Zhu J, Qi J, Wang W, Liu Z Virol J. 2023; 20(1):262.

PMID: 37957672 PMC: 10644626. DOI: 10.1186/s12985-023-02219-4.

Antiviral effect and mechanism of Phillyrin and its reformulated FS21 against influenza.

Chen Y, Wu C, Li H, Powell H, Chen A, Zhu G Influenza Other Respir Viruses. 2023; 17(3):e13112.

PMID: 36875207 PMC: 9975791. DOI: 10.1111/irv.13112.

References

Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R . The efficacy and safety of Favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials. Sci Rep. 2021; 11(1):11022. PMC: 8155021. DOI: 10.1038/s41598-021-90551-6. View

Wang Z, Xia Q, Liu X, Liu W, Huang W, Mei X . Phytochemistry, pharmacology, quality control and future research of Forsythia suspensa (Thunb.) Vahl: A review. J Ethnopharmacol. 2017; 210:318-339. DOI: 10.1016/j.jep.2017.08.040. View

Lutz A, Dyall J, Olivo P, Pekosz A . Virus-inducible reporter genes as a tool for detecting and quantifying influenza A virus replication. J Virol Methods. 2005; 126(1-2):13-20. PMC: 1698269. DOI: 10.1016/j.jviromet.2005.01.016. View

Flannery B, Chung J, Belongia E, McLean H, Gaglani M, Murthy K . Interim Estimates of 2017-18 Seasonal Influenza Vaccine Effectiveness - United States, February 2018. MMWR Morb Mortal Wkly Rep. 2018; 67(6):180-185. PMC: 5815489. DOI: 10.15585/mmwr.mm6706a2. View

Cross K, Burleigh L, Steinhauer D . Mechanisms of cell entry by influenza virus. Expert Rev Mol Med. 2003; 3(21):1-18. DOI: 10.1017/S1462399401003453. View

Pleschka S, Jaskunas R, Engelhardt O, Zurcher T, Palese P, Garcia-Sastre A . A plasmid-based reverse genetics system for influenza A virus. J Virol. 1996; 70(6):4188-92. PMC: 190316. DOI: 10.1128/JVI.70.6.4188-4192.1996. View

Goldhill D, Te Velthuis A, Fletcher R, Langat P, Zambon M, Lackenby A . The mechanism of resistance to favipiravir in influenza. Proc Natl Acad Sci U S A. 2018; 115(45):11613-11618. PMC: 6233120. DOI: 10.1073/pnas.1811345115. View

Lampejo T . Influenza and antiviral resistance: an overview. Eur J Clin Microbiol Infect Dis. 2020; 39(7):1201-1208. PMC: 7223162. DOI: 10.1007/s10096-020-03840-9. View

Blumenkrantz D, Mehoke T, Shaw-Saliba K, Powell H, Wohlgemuth N, Liu H . Identification of H3N2 NA and PB1-F2 genetic variants and their association with disease symptoms during the 2014-15 influenza season. Virus Evol. 2021; 7(1):veab047. PMC: 8197029. DOI: 10.1093/ve/veab047. View

10.

Uyeki T, Bernstein H, Bradley J, Englund J, File T, Fry A . Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa. Clin Infect Dis. 2019; 68(6):895-902. PMC: 6769232. DOI: 10.1093/cid/ciy874. View

11.

Stevaert A, Naesens L . The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design. Med Res Rev. 2016; 36(6):1127-1173. PMC: 5108440. DOI: 10.1002/med.21401. View

12.

Furuta Y, Komeno T, Nakamura T . Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017; 93(7):449-463. PMC: 5713175. DOI: 10.2183/pjab.93.027. View

13.

Uehara T, Hayden F, Kawaguchi K, Omoto S, Hurt A, de Jong M . Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2019; 221(3):346-355. DOI: 10.1093/infdis/jiz244. View

14.

Ko H, Wei B, Chiou W . Dual regulatory effect of plant extracts of Forsythia suspense on RANTES and MCP-1 secretion in influenza A virus-infected human bronchial epithelial cells. J Ethnopharmacol. 2005; 102(3):418-23. DOI: 10.1016/j.jep.2005.06.029. View

15.

Qu X, Li Q, Zhang H, Zhang X, Shi P, Zhang X . Protective effects of phillyrin against influenza A virus in vivo. Arch Pharm Res. 2016; 39(7):998-1005. DOI: 10.1007/s12272-016-0775-z. View

16.

De Clercq E, Li G . Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 2016; 29(3):695-747. PMC: 4978613. DOI: 10.1128/CMR.00102-15. View

17.

Smeeth L, Thomas S, Hall A, Hubbard R, Farrington P, Vallance P . Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004; 351(25):2611-8. DOI: 10.1056/NEJMoa041747. View

18.

Wei T, Tian W, Yan H, Shao G, Xie G . Protective effects of phillyrin on H2O 2-induced oxidative stress and apoptosis in PC12 cells. Cell Mol Neurobiol. 2014; 34(8):1165-73. PMC: 11488936. DOI: 10.1007/s10571-014-0091-4. View

19.

Law A, Yang C, Lau A, Chan G . Antiviral effect of forsythoside A from Forsythia suspensa (Thunb.) Vahl fruit against influenza A virus through reduction of viral M1 protein. J Ethnopharmacol. 2017; 209:236-247. DOI: 10.1016/j.jep.2017.07.015. View

20.

Pan X, Cao X, Li N, Xu Y, Wu Q, Bai J . Forsythin inhibits lipopolysaccharide-induced inflammation by suppressing JAK-STAT and p38 MAPK signalings and ROS production. Inflamm Res. 2014; 63(7):597-608. DOI: 10.1007/s00011-014-0731-7. View