Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19)
Abstract
:1. Introduction
2. Materials and Methods
2.1. Virus, Cell Lines, and Antiviral Agents
2.2. Primary Screening of Broad-Spectrum Antivirals
2.3. Cell Viability Assay
2.4. SARS-CoV-2 Viral Load Reduction Assay
2.5. SARS-CoV-2 Nucleocapsid (N) Antigen Expression Assay
2.6. SARS-CoV-2 Plaque Reduction Assay
2.7. Time-Of-Drug-Addition Assay
3. Results
3.1. Primary Screening
3.2. SARS-CoV-2 N Antigen Expression Assay
3.3. SARS-CoV-2 Viral Load Reduction Assay
3.4. SARS-CoV-2 Plaque Reduction Assay
3.5. Time-Of-Drug-Addition Assay
4. Discussion
Author Contributions
Funding
Conflicts of Interest
References
- Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, J.F.; Kok, K.H.; Zhu, Z.; Chu, H.; To, K.K.; Yuan, S.; Yuen, K.Y. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg. Microbes. Infect. 2020, 9, 221–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- World Health Organization. Coronavirus disease (COVID-19) Situation Report – 95. Available online: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200424-sitrep-95-covid-19.pdf?sfvrsn = e8065831_4 (accessed on 25 April 2020).
- Chan, J.F.; Yuan, S.; Kok, K.H.; To, K.K.; Chu, H.; Yang, J.; Xing, F.; Liu, J.; Yip, C.C.Y.; Poon, R.W.S.; et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020, 395, 514–523. [Google Scholar] [CrossRef] [Green Version]
- Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
- Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.; Hui, D.S.C.; et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [Google Scholar] [CrossRef] [PubMed]
- Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. 2020, ciaa248. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020, 30, 269–271. [Google Scholar] [CrossRef]
- Choy, K.T.; Wong, A.Y.; Kaewpreedee, P.; Sia, S.F.; Chen, D.; Hui, K.P.Y.; Chu, D.K.W.; Chan, M.C.W.; Cheung, P.P.H.; Huang, X.; et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antivir. Res. 2020, 178, 104786. [Google Scholar] [CrossRef] [PubMed]
- Yao, X.; Ye, F.; Zhang, M.; Cui, C.; Huang, B.; Niu, P.; Liu, X.; Zhao, L.; Dong, E.; Song, C.; et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis. 2020, ciaa237. [Google Scholar] [CrossRef] [Green Version]
- Gautret, P.; Lagier, J.C.; Parola, P.; Hoang, V.T.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Vieira, V.E.; et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents 2020, 105949. [Google Scholar] [CrossRef]
- Beigel, J.H.; Tomashek, K.M.; Dodd, L.E.; Mehta, A.K.; Zingman, B.S.; Kalil, A.C.; Hohmann, E.; Chu, H.Y.; Luetkemeyer, A.; Kline, S.; et al. Remdesivir for the Treatment of Covid-19-Preliminary Report. N. Engl. J. Med. 2020. [Google Scholar] [CrossRef] [PubMed]
- Vanden Eynde, J.J. COVID-19: A Brief Overview of the Discovery Clinical Trial. Pharmaceuticals 2020, 13, 65. [Google Scholar] [CrossRef] [PubMed]
- Chu, H.; Chan, J.F.; Yuen, T.T.; Shuai, H.; Yuan, S.; Wang, Y.; Hu, B.; Yip, C.C.Y.; Tsang, J.O.; Huang, X.; et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study. Lancet Microbe. 2020, 1, e14–e23. [Google Scholar]
- Yuan, S.; Chu, H.; Chan, J.F.; Ye, Z.W.; Wen, L.; Yan, B.; Lai, P.; Tee, K.; Huang, J.; Chen, D.; et al. SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target. Nat. Commun. 2019, 10, 120. [Google Scholar] [CrossRef] [PubMed]
- Chan, J.F.; Yip, C.C.; To, K.K.; Tang, T.H.; Wong, S.C.; Leung, K.H.; Fung, A.Y.; Ng, A.C.; Zou, Z.; Tsoi, H.W.; et al. Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens. J. Clin. Microbiol. 2020, 58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, J.F.; Chan, K.H.; Kao, R.Y.; To, K.K.; Zheng, B.J.; Li, C.I.P.; Li, P.T.W.; Dai, J.; Mok, F.K.Y.; Chen, H.; et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 2013, 67, 606–616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, S.Y.; Aliyari, R.; Chikere, K.; Li, G.; Marsden, M.D.; Smith, J.K.; Pernet, O.; Guo, H.; Nusbaum, R.; Zack, J.A.; et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 2013, 38, 92–105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yuan, S.; Chan, J.F.; Den-Haan, H.; Chik, K.K.; Zhang, A.J.; Chan, C.C.; Poon, V.K.; Yip, C.C.Y.; Mak, W.W.; Zhu, Z.; et al. Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo. Antivir. Res. 2017, 145, 33–43. [Google Scholar] [CrossRef] [PubMed]
- Samuel, C.E. Antiviral actions of interferons. Clin. Microbiol. Rev. 2001, 14, 778–809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Retallack, H.; Di Lullo, E.; Arias, C.; Knopp, K.A.; Laurie, M.T.; Sandoval-Espinosa, C.; Leon, W.R.M.; Krencik, R.; Ullian, E.M.; Spatazza, J.; et al. Zika Virus Cell Tropism in the Developing Human Brain and Inhibition by Azithromycin. Proc. Natl. Acad. Sci. USA 2016, 113, 14408–14413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, S.; Lin, B.; Chu, V.; Hu, Z.; Hu, X.; Xiao, J.; Wang, A.Q.; Schweitzer, C.J.; Li, Q.; Imamura, M.; et al. Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Sci. Transl. Med. 2015, 7, 282ra49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Santos, F.R.S.; Nunes, D.A.F.; Lima, W.G.; Davyt, D.; Santos, L.L.; Taranto, A.G.; Ferreira, J.M.S. Identification of Zika Virus NS2B-NS3 Protease Inhibitors by Structure-Based Virtual Screening and Drug Repurposing Approaches. J. Chem. Inf. Model. 2020, 60, 731–737. [Google Scholar] [CrossRef] [PubMed]
- Zumla, A.; Chan, J.F.; Azhar, E.I.; Hui, D.S.; Yuen, K.Y. Coronaviruses - drug discovery and therapeutic options. Nat. Rev. Drug Discov. 2016, 15, 327–347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, C.; Li, F.; Musharrafieh, R.G.; Wang, J. Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance. Antivir. Res. 2016, 133, 62–72. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Wilde, A.H.; Jochmans, D.; Posthuma, C.C.; Zevenhoven-Dobbe, J.C.; Van Nieuwkoop, S.; Bestebroer, T.M. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 2014, 58, 4875–4884. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Savarino, A.; Boelaert, J.R.; Cassone, A.; Majori, G.; Cauda, R. Effects of chloroquine on viral infections: An old drug against today’s diseases? Lancet Infect. Dis. 2003, 3, 722–727. [Google Scholar] [CrossRef]
- Keyaerts, E.; Vijgen, L.; Maes, P.; Neyts, J.; Van Ranst, M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem. Biophys. Res. Commun. 2004, 323, 264–268. [Google Scholar] [CrossRef] [PubMed]
- Pu, S.Y.; Xiao, F.; Schor, S.; Bekerman, E.; Zanini, F.; Barouch-Bentov, R.; Nagamine, C.M.; Einav, S. Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment. Antivir. Res. 2018, 155, 67–75. [Google Scholar] [CrossRef] [PubMed]
- Lupberger, J.; Zeisel, M.B.; Xiao, F.; Thumann, C.; Fofana, I.; Zona, L.; Davis, C.; Mee, C.J.; Turek, M.; Gorke, S.; et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 2011, 17, 589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Murray, J.L.; McDonald, N.J.; Sheng, J.; Shaw, M.W.; Hodge, T.W.; Rubin, D.H.; Brien, W.A.O.; Smee, D.F. Inhibition of Influenza A Virus Replication by Antagonism of a PI3K-AKT-mTOR Pathway Member Identified by Gene-Trap Insertional Mutagenesis. Antivir. Chem. Chemother. 2012, 22, 205–215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Furuta, Y.; Takahashi, K.; Fukuda, Y.; Kuno, M.; Kamiyama, T.; Kozaki, K.; Nomura, N.; Egawa, H.; Minami, S.; Watanabe, Y.; et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother. 2002, 46, 977–981. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guedj, J.; Piorkowski, G.; Jacquot, F.; Madelain, V.; Nguyen, T.H.T.; Rodallec, A.; Gunther, S.; Carbonnelle, C.; Mentré, F.; Raoul, H.; et al. Antiviral Efficacy of Favipiravir Against Ebola Virus: A Translational Study in Cynomolgus Macaques. PLoS Med. 2018, 15, e1002535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D.F.; Barnard, D.L.; Gowen, B.B.; Julander, J.G.; Morrey, J.D. T-705 (Favipiravir) and Related Compounds: Novel Broad-Spectrum Inhibitors of RNA Viral Infections. Antivir. Res. 2009, 82, 95–102. [Google Scholar] [CrossRef] [PubMed]
- Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Jewell, T.; Patel, L.; Ludlum, S.; Drowns, M.; Rahavendran, S.V.; Skor, H.; et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J. Med. Chem. 2009, 52, 1255–1258. [Google Scholar] [CrossRef] [PubMed]
- Warren, T.K.; Wells, J.; Panchal, R.G.; Stuthman, K.S.; Garza, N.L.; Van Tongeren, S.A.; Dong, L.; Retterer, C.J.; Eaton, B.P.; Pegoraro, G.; et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014, 508, 402–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Julander, J.G.; Bantia, S.; Taubenheim, B.R.; Minning, D.M.; Kotian, P.; Morrey, J.D.; Smee, D.F.; Sheridan, W.P.; Babu, Y.S. BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model. Antimicrob. Agents Chemother. 2014, 58, 6607–6614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Taylor, R.; Kotian, P.; Warren, T.; Panchal, R.; Bavari, S.; Julander, J.; Dobo, S.; Rose, A.; El-Kattan, Y.; Taubenheim, B.; et al. BCX4430—A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. J. Infect. Public Health 2016, 9, 220–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Julander, J.G.; Siddharthan, V.; Evans, J.; Taylor, R.; Tolbert, K.; Apuli, C.; Stewart, J.; Stewart, P.; Gebre, M.; Neilson, S.; et al. Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model. Antivir. Res. 2017, 137, 14–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eyer, L.; Zouharová, D.; Širmarová, J.; Fojtíková, M.; Štefánik, M.; Haviernik, J.; Nencka, R.; Clercq, E.; Růžek, D. Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses. Antivir. Res. 2017, 142, 63–67. [Google Scholar] [CrossRef] [PubMed]
- Hou, H.Y.; Lu, W.W.; Wu, K.Y.; Lin, C.W.; Kung, S.H. Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site. J. Gen. Virol. 2016, 97, 1122–1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, J.F.; Yao, Y.; Yeung, M.L.; Deng, W.; Bao, L.; Jia, L.; Li, F.; Xiao, C.; Gao, H.; Yu, P.; et al. Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J. Infect. Dis. 2015, 212, 1904–1913. [Google Scholar] [CrossRef] [PubMed]
- Warren, T.K.; Jordan, R.; Lo, M.K.; Ray, A.S.; Mackman, R.L.; Soloveva, V.; Siegel, D.; Perron, M.; Bannister, R.; Hui, H.C.; et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016, 531, 381–385. [Google Scholar] [CrossRef] [PubMed]
- Lo, M.K.; Jordan, R.; Arvey, A.; Sudhamsu, J.; Shrivastava-Ranjan, P.; Hotard, A.L.; Flint, M.; McMullan, L.K.; Siegel, D.; Clarke, M.O.; et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep. 2017, 7, 43395. [Google Scholar] [CrossRef] [PubMed]
- Sheahan, T.P.; Sims, A.C.; Graham, R.L.; Menachery, V.D.; Gralinski, L.E.; Case, J.B.; Leist, S.R.; Pyrc, K.; Feng, J.Y.; Trantcheva, I.; et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017, 9, eaal3653. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reichard, O.; Yun, Z.B.; Sonnerborg, A.; Weiland, O. Hepatitis C viral RNA titers in serum prior to, during, and after oral treatment with ribavirin for chronic hepatitis C. J. Med. Virol. 1993, 41, 99–102. [Google Scholar] [CrossRef] [PubMed]
- Hall, C.B.; Walsh, E.E.; Hruska, J.F.; Betts, R.F.; Hall, W.J. Ribavirin treatment of experimental respiratory syncytial viral infection. A controlled double-blind study in young adults. JAMA 1983, 249, 2666–2670. [Google Scholar] [CrossRef] [PubMed]
- Ascioglu, S.; Leblebicioglu, H.; Vahaboglu, H.; Chan, K.A. Ribavirin for patients with Crimean-Congo haemorrhagic fever: A systematic review and meta-analysis. J. Antimicrob. Chemother. 2011, 66, 1215–1222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Binford, S.L.; Maldonado, F.; Brothers, M.A.; Weady, P.T.; Zalman, L.S.; Meador, J.W.; Matthews, D.A.; Patick, A.K. Conservation of amino acids in human rhinovirus 3C protease correlates with broad-spectrum antiviral activity of rupintrivir, a novel human rhinovirus 3C protease inhibitor. Antimicrob. Agents Chemother. 2005, 49, 619–626. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rocha-Pereira, J.; Nascimento, M.S.J.; Ma, Q.; Hilgenfeld, R.; Neyts, J.; Jochmans, D. The Enterovirus Protease Inhibitor Rupintrivir Exerts Cross-Genotypic Anti-Norovirus Activity and Clears Cells from the Norovirus Replicon. Antimicrob. Agents Chemother. 2014, 58, 4675–4681. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferenci, P.; Scherzer, T.M.; Kerschner, H.; Rutter, K.; Beinhardt, S.; Hofer, H.; Schöniger-Hekele, M.; Holzmann, H.; Steindl-Munda, P. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008, 135, 1561–1567. [Google Scholar] [CrossRef] [PubMed]
- Cinatl, J.; Morgenstern, B.; Bauer, G.; Chandra, P.; Rabenau, H.; Doerr, H.W. Treatment of SARS with human interferons. Lancet 2003, 362, 293–294. [Google Scholar] [CrossRef]
- Tan, E.L.; Ooi, E.E.; Lin, C.Y.; Tan, H.C.; Ling, A.E.; Lim, B.; Stanton, L.W. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg. Infect. Dis. 2004, 10, 581–586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Haagmans, B.L.; Kuiken, T.; Martina, B.E.; Fouchier, R.A.; Rimmelzwaan, G.F.; Van Amerongen, G.; Van Riel, D.; De Jong, T.; Itamura, S.; Chan, K.; et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat. Med. 2004, 10, 290–293. [Google Scholar] [CrossRef] [PubMed]
- Falzarano, D.; De Wit, E.; Rasmussen, A.L.; Feldmann, F.; Okumura, A.; Scott, D.P.; Brining, D.; Bushmaker, T.; Martellaro, C.; Baseler, L.; et al. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat. Med. 2013, 19, 1313–1317. [Google Scholar] [CrossRef] [PubMed]
- Sainz, B., Jr.; Mossel, E.C.; Peters, C.J.; Garry, R.F. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 2004, 329, 11–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zheng, B.; He, M.L.; Wong, K.L.; Lum, C.T.; Poon, L.L.; Peng, Y.; Guan, Y.; Lin, M.C.M.; Kung, H. Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-alpha/beta) but not by type II interferon (IFN-gamma). J. Interferon Cytokine Res. 2004, 24, 388–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Omrani, A.S.; Saad, M.M.; Baig, K.; Bahloul, A.; Abdul-Matin, M.; Alaidaroos, A.Y.; Almakhlafi, G.A.; Albarrak, M.M.; Memish, Z.A.; Albarrak, A.M. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect. Dis. 2014, 14, 1090–1095. [Google Scholar] [CrossRef] [Green Version]
- Shalhoub, S.; Farahat, F.; Al-Jiffri, A.; Simhairi, R.; Shamma, O.; Siddiqi, N.; Mushtaq, A. IFN-alpha2a or IFN-beta1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: A retrospective study. J. Antimicrob. Chemother. 2015, 70, 2129–2132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chu, H.; Chan, J.F.; Wang, Y.; Yuen, T.T.; Chai, Y.; Hou, Y.; Shuai, H.; Yang, D.; Hu, B.; Huang, X.; et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: An ex vivo study with implications for the pathogenesis of COVID-19. Clin. Infect. Dis. 2020, ciaa410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Djukanovic, R.; Harrison, T.; Johnston, S.L.; Gabbay, F.; Wark, P.; Thomson, N.C.; Niven, R.; Singh, D.; Reddel, H.K.; Davies, D.E.; et al. The effect of inhaled IFN-beta on worsening of asthma symptoms caused by viral infections. A randomized trial. Am. J. Respir. Crit. Care Med. 2014, 190, 145–154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- To, K.K.; Tsang, O.T.; Leung, W.S.; Tam, A.R.; Wu, T.C.; Lung, D.C.; Yip, C.C.Y.; Cai, J.; Chan, J.M.; Chik, T.S.; et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: An observational cohort study. Lancet Infect. Dis. 2020, 20, 565–574. [Google Scholar] [CrossRef] [Green Version]
- Gold, E.S.; Diercks, A.H.; Podolsky, I.; Podyminogin, R.L.; Askovich, P.S.; Treuting, P.M.; Aderem, A. 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc. Natl. Acad. Sci. USA 2014, 111, 10666–10671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Takano, T.; Wakayama, Y.; Doki, T. Endocytic Pathway of Feline Coronavirus for Cell Entry: Differences in Serotype-Dependent Viral Entry Pathway. Pathogens 2019, 8, 300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Y.; Song, Z.; Wang, M.; Lan, M.; Zhang, K.; Jiang, P.; Li, Y.; Bai, J.; Wang, X. Cholesterol 25-hydroxylase negatively regulates porcine intestinal coronavirus replication by the production of 25-hydroxycholesterol. Vet. Microbiol. 2019, 231, 129–138. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Deng, Y.Q.; Wang, S.; Ma, F.; Aliyari, R.; Huang, X.Y.; Zhang, N.; Watanabe, M.; Dong, H.; Dong, P.; et al. 25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model. Immunity 2017, 46, 446–456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schoggins, J.W.; Randall, G. Lipids in innate antiviral defense. Cell Host Microbe. 2013, 14, 379–385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, L.; Bai, Q.; Rodriguez-Agudo, D.; Hylemon, P.B.; Heuman, D.M.; Pandak, W.M.; Ren, S. Regulation of hepatocyte lipid metabolism and inflammatory response by 25-hydroxycholesterol and 25-hydroxycholesterol-3-sulfate. Lipids 2010, 45, 821–832. [Google Scholar] [CrossRef] [PubMed]
- Doms, A.; Sanabria, T.; Hansen, J.N.; Altan-Bonnet, N.; Holm, G.H. 25-Hydroxycholesterol Production by the Cholesterol-25-Hydroxylase Interferon-Stimulated Gene Restricts Mammalian Reovirus Infection. J. Virol. 2018, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hung, I.F.; Lung, K.C.; Tso, E.Y.; Liu, R.; Chung, T.W.; Chu, M.Y.; Ng, Y.; Lo, J.; Chan, J.; Tam, A.R.; et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: An open-label, randomised, phase 2 trial. Lancet 2020, 395, 1695–1704. [Google Scholar] [CrossRef]
Antiviral Agent | Class | Main Clinical or Proposed Use(s) | Examples of Susceptible Viruses | Stage of Development |
---|---|---|---|---|
25-hydroxycholesterol | Oxysterol | Lipid metabolism modulator | VSV, HSV, HIV, MHV68, EBOV, RVFV, RSSEV, Nipah virus [18] | Investigational |
AM580 | Retinoic acid receptor agonist | Anti-neoplastic | SARS-CoV, MERS-CoV, ZIKV, H1N1, EV-A71, AdV [19] | Investigational |
Avonex | Recombinant interferon-β1a | Multiple sclerosis | Broad-spectrum [20] | Clinically approved |
Azithromycin | Macrolide | Antibacterial | ZIKV [21] | Clinically approved |
Betaferon | Recombinant interferon-β1b | Multiple sclerosis | Broad-spectrum [20] | Clinically approved |
Chlorcyclizine | Antihistamine | Allergic rhinitis, urticaria, and emesis | HCV, ZIKV [22,23] | Clinically approved |
Cyclosporine | Calcineurin inhibitor | Immunosuppressant for autoimmune diseases and organ transplantations | SARS-CoV, MERS-CoV, and other CoV’s, influenza A and B viruses [24,25] | Clinically approved |
Chloroquine | 4-Aminoquinoline | Malaria and amoebic liver abscess | SARS-CoV, MERS-CoV, and other CoV’s, HIV, DENV, ZIKV, EBOV, Hendra virus, Nipah virus [24,26,27,28] | Clinically approved |
Erlotinib | Kinase inhibitor | Non-small cell lung cancer and pancreatic cancer | DENV, HCV [29,30] | Clinically approved |
Everolimus | Kinase inhibitor | Organ transplantation and various solid tumors | Cowpox virus, DENV, influenza A virus, rhinovirus, RSV [31] | Clinically approved |
Favipiravir | Nucleoside analogue | Antiviral | Influenza virus, EBOV, falviviruses, arenaviruses, bunyaviruses [32,33,34] | Clinically approved |
Filibuvir | Non-nucleoside polymerase inhibitor | Hepatitis C | HCV [35] | Clinically approved |
Galidesivir | Nucleoside analogue | Antiviral | CoV’s, EBOV, HCV, bunyaviruses, arenaviruses, paramyxoviruses, flaviviruses, phleboviruses [36,37,38,39,40] | Clinical trial |
Idarubicin | Anthracycline | Leukemia | EV-71 [41] | Clinically approved |
Immukin | Recombinant interferon-γ1b | Chronic granulomatous disease and marble bone disease | Broad-spectrum [20] | Clinically approved |
Lopinavir | Protease inhibitor | Human immunodeficiency virus infection | SARS-CoV, MERS-CoV, HIV [24,26,42] | Clinically approved |
Pegasys | Pegylated recombinant interferon-α2a | Chronic hepatitis B and C | Broad-spectrum [20] | Clinically approved |
Rebif | Recombinant interferon-β1a | Multiple sclerosis | Broad-spectrum [20] | Clinically approved |
Remdesivir | Nucleoside analogue | Antiviral | EBOV, CoV’s, filoviruses, pneumoviruses, paramyxoviruses [43,44,45] | Clinical trial/clinically approved (for COVID-19) |
Ribavirin | Nucleoside analogue | Antiviral | CoV’s, HCV, RSV, viral hemorrhagic fevers [24,46,47,48] | Clinically approved |
Rupintrivir | Protease inhibitor | Antiviral | Rhinovirus & picornaviruses, norovirus [49,50] | Investigational |
Silibinin | Flavonoid | Toxic liver damage | HCV [51] | Clinical trial |
Antiviral Agent | CC50 (CellTiterGlo®) a | EC50 (Plaque Reduction Assay) | Select Index (CC50/EC50) |
---|---|---|---|
Pegasys (pegylated IFN-α2a) | >50,000 IU/mL | 1068.0 IU/mL | >46.8 |
Avonex (IFN-β1a) | >50,000 IU/mL | 109.6 IU/mL | >456.2 |
Rebif (IFN-β1a) | >50,000 IU/mL | 70.8 IU/mL | >706.2 |
Betaferon (IFN-β1b) | >50,000 IU/mL | 31.2 IU/mL | >1602.6 |
Immukin (IFN-γ1b) | >50,000 IU/mL | 142.2 IU/mL | >351.6 |
25-hydroxycholesterol | >50 µM | 4.2 µM | >11.9 |
AM580 | 126 µM | 7.6 µM | 16.6 |
Lopinavir | 102 µM | 11.6 µM | 8.8 |
Remdesivir | >100 µM | 1.04 µM | 96.2 |
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Yuan, S.; Chan, C.C.-Y.; Chik, K.K.-H.; Tsang, J.O.-L.; Liang, R.; Cao, J.; Tang, K.; Cai, J.-P.; Ye, Z.-W.; Yin, F.; et al. Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19). Viruses 2020, 12, 628. https://doi.org/10.3390/v12060628
Yuan S, Chan CC-Y, Chik KK-H, Tsang JO-L, Liang R, Cao J, Tang K, Cai J-P, Ye Z-W, Yin F, et al. Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19). Viruses. 2020; 12(6):628. https://doi.org/10.3390/v12060628
Chicago/Turabian StyleYuan, Shuofeng, Chris Chun-Yiu Chan, Kenn Ka-Heng Chik, Jessica Oi-Ling Tsang, Ronghui Liang, Jianli Cao, Kaiming Tang, Jian-Piao Cai, Zi-Wei Ye, Feifei Yin, and et al. 2020. "Broad-Spectrum Host-Based Antivirals Targeting the Interferon and Lipogenesis Pathways as Potential Treatment Options for the Pandemic Coronavirus Disease 2019 (COVID-19)" Viruses 12, no. 6: 628. https://doi.org/10.3390/v12060628