Summary on some antiviral researches

1. Niclosamide: 
 Mode of Action: Neutralization of endosomal pH

*Also affects maturation of Dengue virus (DENV) particles rendering them non-infectious (1). 

 *It is an antiparasitic   drug approved drug for human use. 

2. 1-methylpropyl-2-imidazolyl disulfide (PX-12):   

 Mode of Action:  Reversible inhibition of the thioredoxin system (Trx1 system) causing a slow irreversible thioalkylation of Trx1 (2). 

*Anti-HIV-1 effect. Inhibited the enzymatic activity of Trx1 and the Trx1-dependent disulfide reduction of gp120.  

*Developed as an antitumor agent.

3.  Nitazoxanide (NTZ):   

Mode of Action: Inhibits host ERp57 activity, causing newly synthesized F-protein misfolding, F-aggregate formation and halting F-trafficking to the host plasma membrane as reported in a prototype  paramyxovirus Sendai (SeV) (3). 

 *Inhibits paramyxovirus replication.       

  *Used as treatment for infectious gastroenteritis and anti-viral agent.   
      

4. Arbidol (ARB); also called as Umefinovir:                            

Mode of Action: Blocks virus entry into cells (4). 

 *Inhibits Zika-virus (ZIKV) induced cytopathic effects, blocks multiple steps in ZIKV lifecycle especially virus entry into cells.      

  *Used against seasonal influenza virus (5).

*Often used in diverse families such as Orthomyxoviridae (6), Paramyxoviridae (7), Picornaviridae (8), Bunyaviridae (9), Rhabdoviridae (10), Reoviridae (11), Togaviridae (12), Hepadnaviridae (13), Hepaciviridae (14,17-19) and Filoviridae (15).          

5. Favipiravir (T-705):  

 Mode of Action: Purine analogue.

 *Had potent antiviral activity against henipavirus (Hendra Virus and Nipah Virus). 

Antiviral agent approved in Japan against emerging influenza strains. 

Broad spectrum against RNA viruses (Paramyxoviridae, Filoviridae, Arenaviridae and Bunyavirales).   

6.  Nevirapine (NVP):          

 Mode of Action: Non-nucleoside reverse transcriptase inhibitor in HIV-1.  

*Induces mitochondrial dysregulation in HepG2 cells (21).   

   Side effects: Hepatoxicity

7.  Ribavirin:

 Mode of Action: Precise mechanism is unknown.

However, acts as guanosine nucleoside analogue

*Combination with interferon-α2b may be useful in coronavirus infection (22).    .            

Approved for the treatment of HCV with interferon- α.

                                                                                                                                                  

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REFERENCES:

1.        Jung E, Nam S, Oh H, Jun S, Ro HJ, Kim B, et al. Neutralization of Acidic Intracellular Vesicles by Niclosamide Inhibits Multiple Steps of the Dengue Virus Life Cycle In Vitro. Sci Rep. 2019;9(1):1–12.

2.        Lundberg M, Mattsson Å, Reiser K, Holmgren A, Curbo S. Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells. Sci Rep. 2019;9(1):1–9.

3.        Piacentini S, La Frazia S, Riccio A, Pedersen JZ, Topai A, Nicolotti O, et al. Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: Role of glycoprotein-specific thiol oxidoreductase ERp57. Sci Rep [Internet]. 2018;8(1):1–14. Available from: http://dx.doi.org/10.1038/s41598-018-28172-9

4.         Fink SL, Vojtech L, Wagoner J, Slivinski NSJ, Jackson KJ, Wang R, et al. The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep [Internet]. 2018;8(1):2–10. Available from: http://dx.doi.org/10.1038/s41598-018-27224-4

5.        Blaising, J., Polyak, S. J. & Pecheur, E. I. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res 107, 84–94, https://doi. org/10.1016/j.antiviral.2014.04.006 (2014).

6.        Leneva, I. A., Fediakina, I. T., Gus’kova, T. A. & Glushkov, R. G. Sensitivity of various infuenza virus strains to arbidol. Infuence of arbidol combination with diferent antiviral drugs on reproduction of infuenza virus A. Ter Arkh 77, 84–88 (2005).

7.        Shi, L. et al. Antiviral activity of arbidol against infuenza A virus, respiratory syncytial    virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo. Arch Virol 152, 1447–1455, https://doi.org/10.1007/s00705-007-0974-5 (2007).

8.       Brooks, M. J. et al. Antiviral activity of arbidol, a broad-spectrum drug for use against respiratory viruses, varies according to test conditions. J Med Virol 84, 170–181, https://doi.org/10.1002/jmv.22234 (2012).

9.        Deng, H. Y. et al. Efficacy of arbidol on lethal hantaan virus infections in suckling mice and in vitro. Acta Pharmacol Sin 30, 1015–1024, https://doi.org/10.1038/aps.2009.53 (2009).

10.     Blaising, J. et al. Arbidol inhibits viral entry by interfering with clathrin-dependent trafcking. Antiviral Res 100, 215–219, https:// doi.org/10.1016/j.antiviral.2013.08.008 (2013).

11.      Shi, L. et al. Antiviral activity of arbidol against infuenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo. Arch Virol 152, 1447–1455, https://doi.org/10.1007/s00705-007-0974-5 (2007).

12.     Delogu, I. et al. In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutant. Antiviral Res 90, 99–107, https://doi.org/10.1016/j.antiviral.2011.03.182 (2011).

13.     Zhao, C., Zhao, Y., Chai, H. & Gong, P. Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 5-hydroxy-1H-indole-3- carboxylates. Bioorganic & medicinal chemistry 14, 2552–2558, https://doi.org/10.1016/j.bmc.2005.11.033 (2006).

14.      Blaising, J., Polyak, S. J. & Pecheur, E. I. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res 107, 84–94, https://doi. org/10.1016/j.antiviral.2014.04.006 (2014).

15.      Pecheur, E. I. et al. Te Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses. J Virol, https://doi. org/10.1128/JVI.02077-15 (2016).

16.       Boriskin, Y. S., Leneva, I. A., Pecheur, E. I. & Polyak, S. J. Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem 15, 997–1005 (2008).

17.      Boriskin, Y. S., Pecheur, E. I. & Polyak, S. J. Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection. Virology journal 3, 56, https://doi.org/10.1186/1743-422x-3-56 (2006).

18.        Pecheur, E. I. et al. Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol. Biochemistry 46, 6050–6059, https://doi.org/10.1021/bi700181j (2007).

19.      Teissier, E. et al. Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. PLoS One 6, e15874, https://doi.org/10.1371/journal.pone.0015874 (2011).

20.        Dawes BE, Kalveram B, Ikegami T, Juelich T, Smith JK, Zhang L, et al. Favipiravir (T-705) protects against Nipah virus infection in the hamster model /631/326/22/1295 /631/326/596/1296 /13/106 /14/35 /38/77 /82/51 /96/63 article. Sci Rep [Internet]. 2018;8(1):1–11. Available from: http://dx.doi.org/10.1038/s41598-018-25780-3

21.      Paemanee, A., Sornjai, W., Kittisenachai, S. et al. Nevirapine induced mitochondrial dysfunction in HepG2 cells. Sci Rep 7, 9194 (2017).

22.        Thomas E, Ghany MG, Liang TJ. The application and mechanism of action of ribavirin in therapy of hepatitis C. Antivir Chem Chemother. 2012;23(1):1–12. Published 2012 Sep 25. doi:10.3851/IMP2125

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