Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Favipiravir in SARS-CoV-2 Infection: Is it Worth it?

Author(s): Gaber El-Saber Batiha*, Mohamed Moubarak, Hazem M. Shaheen, Ali M. Zakariya, Ibe M. Usman, Abdur Rauf, Achyut Adhikari, Abhijit Dey, Athanasios Alexiou*, Helal F. Hetta, Ali I. Al-Gareeb and Hayder M. Al-kuraishy

Volume 25, Issue 14, 2022

Published on: 17 June, 2022

Page: [2413 - 2428] Pages: 16

DOI: 10.2174/1386207325666220414111840

Price: $65

Abstract

Favipiravir is a potential antiviral drug undergoing clinical trials to manage various viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Favipiravir possesses antiviral properties against RNA viruses, including SARS-CoV-2. Unfortunately, these viruses do not have authorized antiviral drugs for the management of diseases resulting from their infection, hence the dire need to accentuate the discovery of antiviral drugs that are efficacious and have a broad spectrum. Favipiravir acts primarily by blocking inward and outward movements of the virus from cells. Favipiravir is a prodrug undergoing intracellular phosphorylation and ribosylation to form an active form, favipiravir-RTP, which binds viral RNA-dependent RNA polymerase (RdRp). Considering the novel mechanism of favipiravir action, especially in managing viral infections, it is vital to pay more attention to the promised favipiravir hold in the management of SARS-CoV-2, its efficacy, and dosage regimen, and interactions with other drugs.

In conclusion, favipiravir possesses antiviral properties against RNA viruses, including COVID- 19. Favipiravir is effective against SARS-CoV-2 infection through inhibition of RdRp. Pre-clinical and large-scalp prospective studies are recommended for efficacy and long-term safety of favipiravir in COVID-19.

Keywords: Favipiravir, Covid-19, RNA-dependent RNA polymerase, viral genome, influenza, phosphorylation.

« Previous Next »
Graphical Abstract

[1]
Furuta, Y.; Gowen, B.B.; Takahashi, K.; Shiraki, K.; Smee, D.F.; Barnard, D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res., 2013, 100(2), 446-454.
[http://dx.doi.org/10.1016/j.antiviral.2013.09.015] [PMID: 24084488]
[2]
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.
[http://dx.doi.org/10.2183/pjab.93.027] [PMID: 28769016]
[3]
Boretti, A. Favipiravir use for SARS CoV-2 infection. Pharmacol. Rep., 2020, 72(6), 1542-1552.
[http://dx.doi.org/10.1007/s43440-020-00175-2] [PMID: 33108587]
[4]
Takashita, E. Influenza polymerase inhibitors: Mechanisms of action and resistance. Cold Spring Harb. Perspect. Med., 2021, 11(5), a038687.
[http://dx.doi.org/10.1101/cshperspect.a038687] [PMID: 32122918]
[5]
Łagocka, R.; Dziedziejko, V.; Kłos, P.; Pawlik, A. Favipiravir in therapy of viral infections. J. Clin. Med., 2021, 10(2), 273.
[http://dx.doi.org/10.3390/jcm10020273] [PMID: 33451007]
[6]
Madelain, V.; Guedj, J.; Mentré, F.; Nguyen, T.H.; Jacquot, F.; Oestereich, L.; Kadota, T.; Yamada, K.; Taburet, A.M.; de Lamballerie, X.; Raoul, H. Favipiravir pharmacokinetics in nonhuman primates and insights for future efficacy studies of hemorrhagic fever viruses. Antimicrob. Agents Chemother., 2016, 61(1), e01305-e01316.
[PMID: 27736754]
[7]
Nguyen, T.H.; Guedj, J.; Anglaret, X.; Laouénan, C.; Madelain, V.; Taburet, A.M.; Baize, S.; Sissoko, D.; Pastorino, B.; Rodallec, A.; Piorkowski, G.; Carazo, S.; Conde, M.N.; Gala, J.L.; Bore, J.A.; Carbonnelle, C.; Jacquot, F.; Raoul, H.; Malvy, D.; de Lamballerie, X.; Mentré, F. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl. Trop. Dis., 2017, 11(2), e0005389.
[http://dx.doi.org/10.1371/journal.pntd.0005389] [PMID: 28231247]
[8]
Du, Y.X.; Chen, X.P. Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019‐nCoV infection. Clin. Pharmacol. Ther., 2020, 108(2), 242-247.
[http://dx.doi.org/10.1002/cpt.1844] [PMID: 32246834]
[9]
Antonov, L. Favipiravir tautomerism: A theoretical insight. Theor. Chem. Acc., 2020, 139(8), 145.
[http://dx.doi.org/10.1007/s00214-020-02656-2] [PMID: 32834770]
[10]
Lou, Y.; Liu, L.; Yao, H.; Hu, X.; Su, J.; Xu, K.; Luo, R.; Yang, X.; He, L.; Lu, X.; Zhao, Q.; Liang, T.; Qiu, Y. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: An exploratory randomized, controlled trial. Eur. J. Pharm. Sci., 2021, 157, 105631.
[http://dx.doi.org/10.1016/j.ejps.2020.105631]
[11]
Baburaj, G.; Thomas, L.; Rao, M. Potential drug interactions of repurposed COVID-19 drugs with lung cancer pharmacotherapies. Arch. Med. Res., 2021, 52(3), 261-269.
[http://dx.doi.org/10.1016/j.arcmed.2020.11.006] [PMID: 33257051]
[12]
Ghasemiyeh, P.; Borhani-Haghighi, A.; Karimzadeh, I.; Mohammadi-Samani, S.; Vazin, A.; Safari, A.; Qureshi, A.I. Major neurologic adverse drug reactions, potential drug–drug interactions and pharmacokinetic aspects of drugs used in covid-19 patients with stroke: A narrative review. Ther. Clin. Risk Manag., 2020, 16, 595-605.
[http://dx.doi.org/10.2147/TCRM.S259152] [PMID: 32669846]
[13]
Yamazaki, S.; Suzuki, T.; Sayama, M.; Nakada, T.A.; Igari, H.; Ishii, I. Suspected cholestatic liver injury induced by favipiravir in a patient with COVID-19. J. Infect. Chemother., 2021, 27(2), 390-392.
[http://dx.doi.org/10.1016/j.jiac.2020.12.021] [PMID: 33402301]
[14]
Westover, J.B.; Sefing, E.J.; Bailey, K.W.; Van Wettere, A.J.; Jung, K.H.; Dagley, A.; Wandersee, L.; Downs, B.; Smee, D.F.; Furuta, Y.; Bray, M.; Gowen, B.B. Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res., 2016, 126, 62-68.
[http://dx.doi.org/10.1016/j.antiviral.2015.12.006] [PMID: 26711718]
[15]
Shao, J.; Liang, Y.; Ly, H. Human hemorrhagic Fever causing arenaviruses: Molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathogens, 2015, 4(2), 283-306.
[http://dx.doi.org/10.3390/pathogens4020283] [PMID: 26011826]
[16]
Moreno, H.; Gallego, I.; Sevilla, N.; de la Torre, J.C.; Domingo, E.; Martín, V. Ribavirin can be mutagenic for arenaviruses. J. Virol., 2011, 85(14), 7246-7255.
[http://dx.doi.org/10.1128/JVI.00614-11] [PMID: 21561907]
[17]
Rosenke, K.; Feldmann, H.; Westover, J.B.; Hanley, P.W.; Martellaro, C.; Feldmann, F.; Saturday, G.; Lovaglio, J.; Scott, D.P.; Furuta, Y.; Komeno, T.; Gowen, B.B.; Safronetz, D. Use of favipiravir to treat Lassa virus infection in macaques. Emerg. Infect. Dis., 2018, 24(9), 1696-1699.
[http://dx.doi.org/10.3201/eid2409.180233] [PMID: 29882740]
[18]
Srinivasan, K.; Rao, M. Understanding the clinical utility of favipiravir (T-705) in coronavirus disease of 2019: A review. Ther. Adv. Infect. Dis., 2021, 8, 20499361211063016.
[http://dx.doi.org/10.1177/20499361211063016] [PMID: 34881025]
[19]
Scharton, D.; Bailey, K.W.; Vest, Z.; Westover, J.B.; Kumaki, Y.; Van Wettere, A.; Furuta, Y.; Gowen, B.B. Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antiviral Res., 2014, 104, 84-92.
[http://dx.doi.org/10.1016/j.antiviral.2014.01.016] [PMID: 24486952]
[20]
Johnson, K.N.; Kalveram, B.; Smith, J.K.; Zhang, L.; Juelich, T.; Atkins, C.; Ikegami, T.; Freiberg, A.N. Tilorone-dihydrochloride protects against rift valley fever virus infection and disease in the mouse model. Microorganisms, 2021, 10(1), 10.
[http://dx.doi.org/10.3390/microorganisms10010092] [PMID: 35056541]
[21]
Delang, L.; Abdelnabi, R.; Neyts, J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res., 2018, 153, 85-94.
[http://dx.doi.org/10.1016/j.antiviral.2018.03.003] [PMID: 29524445]
[22]
Debing, Y.; Jochmans, D.; Neyts, J. Intervention strategies for emerging viruses: Use of antivirals. Curr. Opin. Virol., 2013, 3(2), 217-224.
[http://dx.doi.org/10.1016/j.coviro.2013.03.001] [PMID: 23562753]
[23]
Escribano-Romero, E.; Jiménez de Oya, N.; Domingo, E.; Saiz, J.C. Extinction of West Nile virus by favipiravir through lethal mutagenesis. Antimicrob. Agents Chemother., 2017, 61(11), e01400-e01417.
[http://dx.doi.org/10.1128/AAC.01400-17] [PMID: 28848019]
[24]
Delang, L.; Segura Guerrero, N.; Tas, A.; Quérat, G.; Pastorino, B.; Froeyen, M.; Dallmeier, K.; Jochmans, D.; Herdewijn, P.; Bello, F.; Snijder, E.J.; de Lamballerie, X.; Martina, B.; Neyts, J.; van Hemert, M.J.; Leyssen, P. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J. Antimicrob. Chemother., 2014, 69(10), 2770-2784.
[http://dx.doi.org/10.1093/jac/dku209] [PMID: 24951535]
[25]
Oestereich, L.; Lüdtke, A.; Wurr, S.; Rieger, T.; Muñoz-Fontela, C.; Günther, S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res., 2014, 105, 17-21.
[http://dx.doi.org/10.1016/j.antiviral.2014.02.014] [PMID: 24583123]
[26]
Bai, C.Q.; Mu, J.S.; Kargbo, D.; Song, Y.B.; Niu, W.K.; Nie, W.M.; Kanu, A.; Liu, W.W.; Wang, Y.P.; Dafae, F.; Yan, T.; Hu, Y.; Deng, Y.Q.; Lu, H.J.; Yang, F.; Zhang, X.G.; Sun, Y.; Cao, Y.X.; Su, H.X.; Sun, Y.; Liu, W.S.; Wang, C.Y.; Qian, J.; Liu, L.; Wang, H.; Tong, Y.G.; Liu, Z.Y.; Chen, Y.S.; Wang, H.Q.; Kargbo, B.; Gao, G.F.; Jiang, J.F. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)—Sierra Leone, 2014. Clin. Infect. Dis., 2016, 63(10), 1288-1294.
[http://dx.doi.org/10.1093/cid/ciw571] [PMID: 27553371]
[27]
Kiso, M.; Takahashi, K.; Sakai-Tagawa, Y.; Shinya, K.; Sakabe, S.; Le, Q.M.; Ozawa, M.; Furuta, Y.; Kawaoka, Y. T-705 (favipiravir) activity against lethal H5N1 influenza a viruses. Proc. Natl. Acad. Sci. USA, 2010, 107(2), 882-887.
[http://dx.doi.org/10.1073/pnas.0909603107] [PMID: 20080770]
[28]
Smee, D.F.; Hurst, B.L.; Egawa, H.; Takahashi, K.; Kadota, T.; Furuta, Y. Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells. J. Antimicrob. Chemother., 2009, 64(4), 741-746.
[http://dx.doi.org/10.1093/jac/dkp274] [PMID: 19643775]
[29]
Al-kuraishy, H.M.; Al-Maiahy, T.J.; Al-Gareeb, A.I.; Musa, R.A.; Ali, Z.H. COVID-19 pneumonia in an Iraqi pregnant woman with preterm delivery. Asian Pac. J. Reprod., 2020, 9(3), 156.
[http://dx.doi.org/10.4103/2305-0500.282984]
[30]
Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; Li, X.; Xia, J.; Chen, N.; Xiang, J.; Yu, T.; Bai, T.; Xie, X.; Zhang, L.; Li, C.; Yuan, Y.; Chen, H.; Li, H.; Huang, H.; Tu, S.; Gong, F.; Liu, Y.; Wei, Y.; Dong, C.; Zhou, F.; Gu, X.; Xu, J.; Liu, Z.; Zhang, Y.; Li, H.; Shang, L.; Wang, K.; Li, K.; Zhou, X.; Dong, X.; Qu, Z.; Lu, S.; Hu, X.; Ruan, S.; Luo, S.; Wu, J.; Peng, L.; Cheng, F.; Pan, L.; Zou, J.; Jia, C.; Wang, J.; Liu, X.; Wang, S.; Wu, X.; Ge, Q.; He, J.; Zhan, H.; Qiu, F.; Guo, L.; Huang, C.; Jaki, T.; Hayden, F.G.; Horby, P.W.; Zhang, D.; Wang, C. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med., 2020, 382(19), 1787-1799.
[http://dx.doi.org/10.1056/NEJMoa2001282] [PMID: 32187464]
[31]
Zuo, Y.; Liu, Y.; Zhong, Q.; Zhang, K.; Xu, Y.; Wang, Z. Lopinavir/ritonavir and interferon combination therapy may help shorten the duration of viral shedding in patients with COVID-19: A retrospective study in two designated hospitals in Anhui, China. J. Med. Virol., 2020, 92(11), 2666-2674.
[http://dx.doi.org/10.1002/jmv.26127] [PMID: 32492211]
[32]
Behzadi, M.A.; Leyva-Grado, V.H. Overview of current therapeutics and novel candidates against influenza, respiratory syncytial virus, and Middle East respiratory syndrome coronavirus infections. Front. Microbiol., 2019, 10, 1327.
[http://dx.doi.org/10.3389/fmicb.2019.01327] [PMID: 31275265]
[33]
Al-Kuraishy, H.M.; Al-Gareeb, A.I.; Faidah, H.; Al-Maiahy, T.J.; Cruz-Martins, N.; Batiha, G.E. The looming effects of estrogen in Covid-19: A rocky rollout. Front. Nutr., 2021, 8, 649128.
[http://dx.doi.org/10.3389/fnut.2021.649128] [PMID: 33816542]
[34]
Aktaş, A.; Tüzün, B.; Aslan, R.; Sayin, K.; Ataseven, H. New antiviral drugs for the treatment of COVID-19 instead of favipiravir. J. Biomol. Struct. Dyn., 2020, 11, 1-1.
[PMID: 32783586]
[35]
Cai, Q.; Yang, M.; Liu, D.; Chen, J.; Shu, D.; Xia, J.; Liao, X.; Gu, Y.; Cai, Q.; Yang, Y.; Shen, C.; Li, X.; Peng, L.; Huang, D.; Zhang, J.; Zhang, S.; Wang, F.; Liu, J.; Chen, L.; Chen, S.; Wang, Z.; Zhang, Z.; Cao, R.; Zhong, W.; Liu, Y.; Liu, L. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering (Beijing), 2020, 6(10), 1192-1198.
[http://dx.doi.org/10.1016/j.eng.2020.03.007] [PMID: 32346491]
[36]
Sisay, M. 3CLpro inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials. Pharmacol. Res., 2020, 156, 104779.
[http://dx.doi.org/10.1016/j.phrs.2020.104779] [PMID: 32247821]
[37]
Joshi, S.; Parkar, J.; Ansari, A.; Vora, A.; Talwar, D.; Tiwaskar, M.; Patil, S.; Barkate, H. Role of favipiravir in the treatment of COVID-19. Int. J. Infect. Dis., 2021, 102, 501-508.
[http://dx.doi.org/10.1016/j.ijid.2020.10.069] [PMID: 33130203]
[38]
Kocayiğit, H.; Özmen Süner, K.; Tomak, Y.; Demir, G.; Yaylacı, S.; Dheir, H.; Güçlü, E.; Erdem, A.F. Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID-19. J. Clin. Pharm. Ther., 2021, 46(2), 454-459.
[http://dx.doi.org/10.1111/jcpt.13305] [PMID: 33128482]
[39]
Dauby, N.; Van Praet, S.; Vanhomwegen, C.; Veliziotis, I.; Konopnicki, D.; Roman, A. Tolerability of favipiravir therapy in critically ill patients with COVID-19: A report of four cases. J. Med. Virol., 2021, 93(2), 689-691.
[http://dx.doi.org/10.1002/jmv.26488] [PMID: 32886358]
[40]
Udwadia, Z.F.; Singh, P.; Barkate, H.; Patil, S.; Rangwala, S.; Pendse, A.; Kadam, J.; Wu, W.; Caracta, C.F.; Tandon, M. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int. J. Infect. Dis., 2021, 103, 62-71.
[http://dx.doi.org/10.1016/j.ijid.2020.11.142] [PMID: 33212256]
[41]
Chen, C.; Huang, J.; Cheng, Z.; Wu, J.; Chen, S.; Zhang, Y.; Chen, B.; Lu, M.; Luo, Y.; Zhang, J.; Yin, P. Favipiravir versus arbidol for COVID-19: A randomized clinical trial Med; Rxiv, 2020.
[http://dx.doi.org/10.1101/2020.03.17.20037432]
[42]
Al-Kuraishy, H.M.; Al-Gareeb, A.I.; Alzahrani, K.J.; Alexiou, A.; Batiha, G.E. Niclosamide for Covid-19: Bridging the gap. Mol. Biol. Rep., 2021, 48(12), 8195-8202.
[http://dx.doi.org/10.1007/s11033-021-06770-7] [PMID: 34664162]
[43]
Al-Kuraishy, H.M.; Al-Gareeb, A.I.; Alkazmi, L.; Alexiou, A.; Batiha, G.E. Levamisole therapy in COVID-19. Viral Immunol., 2021, 34(10), 722-725.
[http://dx.doi.org/10.1089/vim.2021.0042] [PMID: 34388031]
[44]
Çap, M.; Bilge, Ö.; Işık, F.; Burak, C.; Karagöz, A.; İnci, Ü.; Akyüz, A.; Aslan, B.; Altıntaş, B.; Altındağ, R.; Kaya, İ.; Adıyaman, M.Ş.; Süleymanoğlu, M.; Kaya, Ş.; Baysal, E. The effect of favipiravir on QTc interval in patients hospitalized with coronavirus disease 2019. J. Electrocardiol., 2020, 63, 115-119.
[http://dx.doi.org/10.1016/j.jelectrocard.2020.10.015] [PMID: 33181454]
[45]
Amawi, H.; Abu Deiab, G.I.; A Aljabali, A.A.; Dua, K.; Tambuwala, M.M COVID-19 pandemic: An overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics. Ther. Deliv., 2020, 11(4), 245-268.
[http://dx.doi.org/10.4155/tde-2020-0035] [PMID: 32397911]
[46]
Mishima, E.; Anzai, N.; Miyazaki, M.; Abe, T. Uric acid elevation by favipiravir, an antiviral drug. Tohoku J. Exp. Med., 2020, 251(2), 87-90.
[http://dx.doi.org/10.1620/tjem.251.87] [PMID: 32536670]
[47]
Shiraki, K.; Daikoku, T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol. Ther., 2020, 209, 107512.
[http://dx.doi.org/10.1016/j.pharmthera.2020.107512] [PMID: 32097670]
[48]
Jin, Z.; Kinkade, A.; Behera, I.; Chaudhuri, S.; Tucker, K.; Dyatkina, N.; Rajwanshi, V.K.; Wang, G.; Jekle, A.; Smith, D.B.; Beigelman, L.; Symons, J.A.; Deval, J. Structure-activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs. Antiviral Res., 2017, 143, 151-161.
[http://dx.doi.org/10.1016/j.antiviral.2017.04.005] [PMID: 28412183]
[49]
dos Santos, GC; Martins, LM; Bregadiolli, BA; Moreno, VF; da Silva-Filho, LC; da Silva, BH Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications. J. Heterocycl. Chem., 2021, 58(12), 2226-2260.
[50]
da Silva, G. Protonation, tautomerism, and base pairing of the antiviral favipiravir (T-705). ChemRxiv, 2020. [Epub ahead of Print].
[http://dx.doi.org/10.26434/chemrxiv.12229122.v2]

Rights & Permissions Print Cite
Article Metrics
21
3
© 2024 Bentham Science Publishers | Privacy Policy