Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cells and Compounds
2.2. Cytotoxicity Assay
2.3. Virus Infection and Drug Treatment
2.4. Plaque Assay
2.5. Data and Statistical Analysis
3. Results
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Baud, D.; Qi, X.; Nielsen-Saines, K.; Musso, D.; Pomar, L.; Favre, G. Real estimates of mortality following COVID-19 infection. Lancet Infect. Dis. 2020, 20, 773. [Google Scholar] [CrossRef] [Green Version]
- Rajgor, D.D.; Lee, M.H.; Archuleta, S.; Bagdasarian, N.; Quek, S.C. The many estimates of the COVID-19 case fatality rate. Lancet Infect. Dis. 2020, 20, 776–777. [Google Scholar] [CrossRef] [Green Version]
- Corman, V.M.; Lienau, J.; Witzenrath, M. Coronaviruses as the cause of respiratory infections. Internist 2019, 60, 1136–1145. [Google Scholar] [CrossRef] [Green Version]
- Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. J. Am. Med. Assoc. 2020, 323, 1061–1069. [Google Scholar] [CrossRef] [PubMed]
- Tang, N.; Li, D.; Wang, X.; Sun, Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020, 18, 844–847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2018, 18, 41–58. [Google Scholar] [CrossRef]
- Ianevski, A.; Yao, R.; Fenstad, M.H.; Biza, S.; Zusinaite, E.; Reisberg, T.; Lysvand, H.; Løseth, K.; Landsem, V.M.; Malmring, J.F.; et al. Potential antiviral options against SARS-CoV-2 infection. Viruses 2020, 12, 642. [Google Scholar] [CrossRef] [PubMed]
- Gordon, C.J.; Tchesnokov, E.P.; Woolner, E.; Perry, J.K.; Feng, J.Y.; Porter, D.P.; Götte, M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J. Biol. Chem. 2020, 295, 6785–6797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Agostini, M.L.; Andres, E.L.; Sims, A.C.; Graham, R.L.; Sheahan, T.P.; Lu, X.; Smith, E.C.; Case, J.B.; Feng, J.Y.; Jordan, R.; et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio 2018, 9, e00221-18. [Google Scholar] [CrossRef] [Green Version]
- Siegel, D.; Hui, H.C.; Doerffler, E.; Clarke, M.O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B.; et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J. Med. Chem. 2017, 60, 1648–1661. [Google Scholar] [CrossRef] [Green Version]
- Pruijssers, A.J.; George, A.S.; Schäfer, A.; Leist, S.R.; Gralinksi, L.E.; Dinnon, K.H.; Yount, B.L.; Agostini, M.L.; Stevens, L.J.; Chappell, J.D.; et al. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Rep. 2020, 32, 107940. [Google Scholar] [CrossRef]
- Li, Y.; Cao, L.; Li, G.; Cong, F.; Li, Y.; Sun, J.; Luo, Y.; Chen, G.; Li, G.; Wang, P.; et al. Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mice Models. bioRxiv 2020. [Google Scholar] [CrossRef]
- Goldman, J.D.; Lye, D.C.B.; Hui, D.S.; Marks, K.M.; Bruno, R.; Montejano, R.; Spinner, C.D.; Galli, M.; Ahn, M.-Y.; Nahass, R.G.; et al. Remdesivir for 5 or 10 Days in Patients with Severe COVID-19. N. Engl. J. Med. 2020, 383, 1827–1837. [Google Scholar] [CrossRef]
- Tempestilli, M.; Caputi, P.; Avataneo, V.; Notari, S.; Forini, O.; Scorzolini, L.; Marchioni, L.; Bartoli, T.A.; Castilletti, C.; Lalle, E.; et al. Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19. J. Antimicrob. Chemother. 2020, 75, 2977–2980. [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]
- Williamson, B.N.; Feldmann, F.; Schwarz, B.; Meade-White, K.; Porter, D.P.; Schulz, J.; van Doremalen, N.; Leighton, I.; Yinda, C.K.; Pérez-Pérez, L.; et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature 2020, 585, 273–276. [Google Scholar] [CrossRef] [PubMed]
- Yan, V.C.; Muller, F.L. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for COVID-19 Treatment. ACS Med. Chem. Lett. 2020, 11, 1361–1366. [Google Scholar] [CrossRef]
- 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]
- Schwegmann, A.; Brombacher, F. Host-directed drug targeting of factors hijacked by pathogens. Sci. Signal. 2008, 1, re8. [Google Scholar] [CrossRef]
- Zumla, A.; Rao, M.; Wallis, R.S.; Kaufmann, S.H.E.; Rustomjee, R.; Mwaba, P.; Vilaplana, C.; Yeboah-Manu, D.; Chakaya, J.; Ippolito, G.; et al. Host-directed therapies for infectious diseases: Current status, recent progress, and future prospects. Lancet Infect. Dis. 2016, 16, e47–e63. [Google Scholar] [CrossRef] [Green Version]
- Zumla, A.; Hui, D.S.; Azhar, E.I.; Memish, Z.A.; Maeurer, M. Reducing mortality from 2019-nCoV: Host-directed therapies should be an option. Lancet 2020, 395, e35–e36. [Google Scholar] [CrossRef] [Green Version]
- Kornhuber, J.; Tripal, P.; Reichel, M.; Mühle, C.; Rhein, C.; Muehlbacher, M.; Groemer, T.W.; Gulbins, E. Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A Novel Pharmacological Group of Drugs with Broad Clinical Applications. Cell. Physiol. Biochem. 2010, 25, 9–20. [Google Scholar] [CrossRef] [PubMed]
- Schloer, S.; Brunotte, L.; Goretzko, J.; Mecate-Zambrano, A.; Korthals, N.; Gerke, V.; Ludwig, S.; Rescher, U. Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg. Microbes Infect. 2020, 1–26. [Google Scholar] [CrossRef]
- Schloer, S.; Goretzko, J.; Pleschka, S.; Ludwig, S.; Rescher, U. Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection. Viruses 2020, 12, 703. [Google Scholar] [CrossRef] [PubMed]
- Ianevski, A.; He, L.; Aittokallio, T.; Tang, J. SynergyFinder: A web application for analyzing drug combination dose-response matrix data. Bioinformatics 2017, 33, 2413–2415. [Google Scholar] [CrossRef]
- Malyutina, A.; Majumder, M.M.; Wang, W.; Pessia, A.; Heckman, C.A.; Tang, J. Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer. PLoS Comput. Biol. 2019, 15, e1006752. [Google Scholar] [CrossRef] [Green Version]
- Schloer, S.; Brunotte, L.; Mecate-Zambrano, A.; Zheng, S.; Tang, J.; Ludwig, S.; Rescher, U. Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br. J. Pharmacol. 2021, 178, 2339–2350. [Google Scholar] [CrossRef] [PubMed]
- Yi, C.; Sun, X.; Ye, J.; Ding, L.; Liu, M.; Yang, Z.; Lu, X.; Zhang, Y.; Ma, L.; Gu, W.; et al. Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies. Cell. Mol. Immunol. 2020, 17, 621–630. [Google Scholar] [CrossRef] [PubMed]
- Davies, N.G.; Jarvis, C.I.; van Zandvoort, K.; Clifford, S.; Sun, F.Y.; Funk, S.; Medley, G.; Jafari, Y.; Meakin, S.R.; Lowe, R.; et al. Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature 2021, 593, 270–274. [Google Scholar] [CrossRef]
- Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E.J.; Msomi, N.; et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv 2020. [Google Scholar] [CrossRef]
- Kirby, T. New variant of SARS-CoV-2 in UK causes surge of COVID-19. Lancet. Respir. Med. 2021, 9, e20–e21. [Google Scholar] [CrossRef]
- Palella, F.J.; Delaney, K.M.; Moorman, A.C.; Loveless, M.O.; Fuhrer, J.; Satten, G.A.; Aschman, D.J.; Holmberg, S.D. Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. N. Engl. J. Med. 1998, 338, 853–860. [Google Scholar] [CrossRef]
- Naggie, S.; Muir, A.J. Oral Combination Therapies for Hepatitis C Virus Infection: Successes, Challenges, and Unmet Needs. Annu. Rev. Med. 2017, 68, 345–358. [Google Scholar] [CrossRef] [PubMed]
- Hayden, F.G. Combination antiviral therapy for respiratory virus infections. Antiviral Res. 1996, 29, 45–48. [Google Scholar] [CrossRef]
- Korba, B.E.; Cote, P.; Hornbuckle, W.; Schinazi, R.; Gerin, J.L.; Tennant, B.C. Enhanced antiviral benefit of combination therapy with lamivudine and famciclovir against WHV replication in chronic WHV carrier woodchucks. Antiviral Res. 2000, 45, 19–32. [Google Scholar] [CrossRef]
- Qian, X.J.; Zhu, Y.Z.; Zhao, P.; Qi, Z.T. Entry inhibitors: New advances in HCV treatment. Emerg. Microbes Infect. 2016, 5, e3. [Google Scholar] [CrossRef] [PubMed]
- Crouchet, E.; Wrensch, F.; Schuster, C.; Zeisel, M.B.; Baumert, T.F. Host-targeting therapies for hepatitis C virus infection: Current developments and future applications. Therap. Adv. Gastroenterol. 2018, 11, 1–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pirrone, V.; Thakkar, N.; Jacobson, J.M.; Wigdahl, B.; Krebs, F.C. Combinatorial approaches to the prevention and treatment of HIV-1 infection. Antimicrob. Agents Chemother. 2011, 55, 1831–1842. [Google Scholar] [CrossRef] [Green Version]
- Strasfeld, L.; Chou, S. Antiviral drug resistance: Mechanisms and clinical implications. Infect. Dis. Clin. N. Am. 2010, 24, 809–833. [Google Scholar] [CrossRef]
- Kim, S.G.; Hwang, Y.H.; Shin, Y.H.; Kim, S.W.; Jung, W.S.; Kim, S.M.; Oh, J.M.; Lee, N.Y.; Kim, M.J.; Cho, K.S.; et al. Occurrence and characterization of oseltamivir-resistant influenza virus in children between 2007–2008 and 2008–2009 seasons. Korean J. Pediatr. 2013, 56, 165–175. [Google Scholar] [CrossRef]
- Kuritzkes, D.R. Drug resistance in HIV-1. Curr. Opin. Virol. 2011, 1, 582–589. [Google Scholar] [CrossRef]
- Kiso, M.; Yamayoshi, S.; Kawaoka, Y. Triple combination therapy of favipiravir plus two monoclonal antibodies eradicates influenza virus from nude mice. Commun. Biol. 2020, 3, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Zumla, A.; Memish, Z.A.; Maeurer, M.; Bates, M.; Mwaba, P.; Al-Tawfiq, J.A.; Denning, D.W.; Hayden, F.G.; Hui, D.S. Emerging novel and antimicrobial-resistant respiratory tract infections: New drug development and therapeutic options. Lancet Infect. Dis. 2014, 14, 1136–1149. [Google Scholar] [CrossRef]
- Mhamdi, Z.; Fausther-Bovendo, H.; Uyar, O.; Carbonneau, J.; Venable, M.-C.; Abed, Y.; Kobinger, G.; Boivin, G.; Baz, M. Effects of Different Drug Combinations in Immunodeficient Mice Infected with an Influenza A/H3N2 Virus. Microorganisms 2020, 8, 1968. [Google Scholar] [CrossRef]
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Moore, M.J.; Vasllieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greeneugh, T.C.; et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003, 426, 450–454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215–220. [Google Scholar] [CrossRef] [Green Version]
- Ou, X.; Liu, Y.; Lei, X.; Li, P.; Mi, D.; Ren, L.; Guo, L.; Guo, R.; Chen, T.; Hu, J.; et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020, 11, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Brown, A.J.; Won, J.J.; Graham, R.L.; Dinnon, K.H.; Sims, A.C.; Feng, J.Y.; Cihlar, T.; Denison, M.R.; Baric, R.S.; Sheahan, T.P. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019, 169, 104541. [Google Scholar] [CrossRef]
- Murakami, E.; Wang, T.; Babusis, D.; Lepist, E.I.; Sauer, D.; Park, Y.; Vela, J.E.; Shih, R.; Birkus, G.; Stefanidis, D.; et al. Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620. Antimicrob. Agents Chemother. 2014, 58, 1943–1951. [Google Scholar] [CrossRef] [Green Version]
- Wichmann, D.; Sperhake, J.P.; Lütgehetmann, M.; Steurer, S.; Edler, C.; Heinemann, A.; Heinrich, F.; Mushumba, H.; Kniep, I.; Schröder, A.S.; et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann. Intern. Med. 2020, 173, 268–277. [Google Scholar] [CrossRef]
- Bieganowski, P.; Garrison, P.N.; Hodawadekar, S.C.; Faye, G.; Barnes, L.D.; Brenner, C. Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3. J. Biol. Chem. 2002, 277, 10852–10860. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chou, T.F.; Baraniak, J.; Kaczmarek, R.; Zhou, X.; Cheng, J.; Ghosh, B.; Wagner, C.R. Phosphoramidate pronucleotides: A comparison of the phosphoramidase substrate specificity of human and Escherichia coli histidine triad nucleotide binding proteins. Mol. Pharm. 2007, 4, 208–217. [Google Scholar] [CrossRef]
- 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, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Yan, V.C.; Khadka, S.; Arthur, K.; Pham, C.-D.; Yan, A.J.; Ackroyd, J.J.; Georgiou, D.K. Pharmacokinetics of Orally Administered GS-441524 in Dogs. bioRxiv 2021. [Google Scholar] [CrossRef]
- Pedersen, N.C.; Perron, M.; Bannasch, M.; Montgomery, E.; Murakami, E.; Liepnieks, M.; Liu, H. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J. Feline Med. Surg. 2019, 21, 271–281. [Google Scholar] [CrossRef] [Green Version]
- Preskorn, S.H.; Silkey, B.; Beber, J.; Dorey, C. Antidepressant response and plasma concentrations of fluoxetine. Ann. Clin. Psychiatry 1991, 3, 147–151. [Google Scholar] [CrossRef]
- Pope, S.; Zaraa, S.G. Serum fluoxetine and norfluoxetine levels support the safety of fluoxetine in overdose. Ann. Gen. Psychiatry 2016, 15, 30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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—Final Report. N. Engl. J. Med. 2020, 383, 1813–1826. [Google Scholar] [CrossRef] [PubMed]
- Kalil, A.C.; Patterson, T.F.; Mehta, A.K.; Tomashek, K.M.; Wolfe, C.R.; Ghazaryan, V.; Marconi, V.C.; Ruiz-Palacios, G.M.; Hsieh, L.; Kline, S.; et al. Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19. N. Engl. J. Med. 2020, 384, 795–807. [Google Scholar] [CrossRef]
- Kumar, D.; Trivedi, N. Disease-drug and drug-drug interaction in COVID-19: Risk and assessment. Biomed. Pharmacother. 2021, 139, 111642. [Google Scholar] [CrossRef] [PubMed]
- Yang, K. What Do We Know About Remdesivir Drug Interactions? Clin. Transl. Sci. 2020, 13, 842–844. [Google Scholar] [CrossRef] [PubMed]
- Humeniuk, R.; Mathias, A.; Kirby, B.J.; Lutz, J.D.; Cao, H.; Osinusi, A.; Babusis, D.; Porter, D.; Wei, X.; Ling, J.; et al. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor. Clin. Pharmacokinet. 2021, 60, 569–583. [Google Scholar] [CrossRef]
- Sager, J.E.; Lutz, J.D.; Foti, R.S.; Davis, C.; Kunze, K.L.; Isoherranen, N. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: In vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clin. Pharmacol. Ther. 2014, 95, 653–662. [Google Scholar] [CrossRef] [Green Version]
- Deodhar, M.; Al Rihani, S.B.; Darakjian, L.; Turgeon, J.; Michaud, V. Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition. Pharmaceutics 2021, 13, 148. [Google Scholar] [CrossRef] [PubMed]
- Plasencia-García, B.O.; Rico-Rangel, M.I.; Rodríguez-Menéndez, G.; Rubio-García, A.; Torelló-Iserte, J.; Crespo-Facorro, B. Drug-drug Interactions between COVID-19 Treatments and Antidepressants, Mood Stabilizers/Anticonvulsants, and Benzodiazepines: Integrated Evidence from 3 Databases. Pharmacopsychiatry 2021. [Google Scholar] [CrossRef] [PubMed]
- Brambilla, P.; Cipriani, A.; Hotopf, M.; Barbui, C. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: A meta-analysis of clinical trial data. Pharmacopsychiatry 2005, 38, 69–77. [Google Scholar] [CrossRef]
- Cooper, G.L. The safety of fluoxetine—An update. Br. J. Psychiatry 1988, 153, 77–86. [Google Scholar] [CrossRef]
- Drugs.com. Drug Interaction Checker from Drugs.com; c1996–2018 [Last Updated: 2 Nov 2020]. Available online: https://www.drugs.com/drug_interactions.html (accessed on 21 January 2021).
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Brunotte, L.; Zheng, S.; Mecate-Zambrano, A.; Tang, J.; Ludwig, S.; Rescher, U.; Schloer, S. Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro. Pharmaceutics 2021, 13, 1400. https://doi.org/10.3390/pharmaceutics13091400
Brunotte L, Zheng S, Mecate-Zambrano A, Tang J, Ludwig S, Rescher U, Schloer S. Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro. Pharmaceutics. 2021; 13(9):1400. https://doi.org/10.3390/pharmaceutics13091400
Chicago/Turabian StyleBrunotte, Linda, Shuyu Zheng, Angeles Mecate-Zambrano, Jing Tang, Stephan Ludwig, Ursula Rescher, and Sebastian Schloer. 2021. "Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro" Pharmaceutics 13, no. 9: 1400. https://doi.org/10.3390/pharmaceutics13091400