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. 2020 Oct 18;12(10):1178.
doi: 10.3390/v12101178.

Identification and Tracking of Antiviral Drug Combinations

Aleksandr Ianevski  1 , Rouan Yao  1 , Svetlana Biza  1 , Eva Zusinaite  2 , Andres Mannik  3 , Gaily Kivi  3 , Anu Planken  3 , Kristiina Kurg  3 , Eva-Maria Tombak  3 , Mart Ustav Jr  3 , Nastassia Shtaida  2 , Evgeny Kulesskiy  4 , Eunji Jo  5 , Jaewon Yang  5 , Hilde Lysvand  1 , Kirsti Løseth  1 , Valentyn Oksenych  1 , Per Arne Aas  1 , Tanel Tenson  2 , Astra Vitkauskienė  6 , Marc P Windisch  5 , Mona Høysæter Fenstad  1   7 , Svein Arne Nordbø  1   8 , Mart Ustav  3 , Magnar Bjørås  1 , Denis E Kainov  1   2   4
Affiliations

Identification and Tracking of Antiviral Drug Combinations

Aleksandr Ianevski et al. Viruses. .

Abstract

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.

Keywords: antiviral drug combinations; antivirals; broad-spectrum antivirals; virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Discovery and development of antiviral drug combinations for treatment of viral infections.
Figure 2
Figure 2
Combinations of nelfinavir with convalescent serum, neutralizing antibody, EIDD-2801, or remdesivir rescue Calu-3 cells from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated death and inhibit virus replication. (A) The interaction landscapes of one of the combinations measured using a CTG assay on SARS-CoV-2- and mock-infected cells. (B) The interaction landscape showing selectivity and synergy of the drug combination. (C) Synergy scores were calculated for efficacy (SARS-CoV-2-infected) and selectivity (SARS-CoV-2-infected–Mock-infected) dose-response matrices for drug combinations. (D) The effects of 1 µM nelfinavir plus 0.1% DMSO, 2 mg/mL G614, 1 µM EIDD-2801, 1 µM remdesivir or 2 ng/mL 23G7 antibody on viral replication measured by plaque reduction assay.
Figure 3
Figure 3
Combinations of vemurafenib with other antiviral agents rescue A549 cells from echovirus 1 (EV1)-mediated death and inhibit virus replication. (A) The interaction landscapes of one of the drug combinations measured using a CTG assay on EV1- and mock-infected cells. (B) The interaction landscape showing selectivity and synergy of the drug combination. (C) Synergy scores were calculated for efficacy (EV1-infected) and selectivity (EV1-infected–Mock) dose-response matrices for drug combinations. (D) The effects of 5 µM vemurafenib plus 0.1% DMSO, 0.2 µM emetine, 0.2 µM homoharringtonine, 0.2 µM obatoclax, 1 µL gemcitabine, 0.1 µL anisomycin and 1 µL cycloheximide on viral replication measured by plaque reduction assay.
Figure 4
Figure 4
Combination of sofosbuvir and brequinar or niclosamide inhibit HCV-mediated GFP expression in Huh-7.5 cells. (A,C) The interaction landscapes measured using a GFP-expressing reporter virus. (B,D) The interaction landscapes of two drugs measured using CTG assay on mock-infected cells.
Figure 5
Figure 5
Combinations of monensin with lamivudine or tenofovir inhibit human immunodeficiency virus 1 (HIV-1)-mediated luciferase expression in TZM-bl cells. (A,C) The interaction drug combination landscapes measured as 6 × 6 dose-response matrices using an HIV-1 virus and reporter cell line expressing luciferase. (B,D) The interaction drug combination landscapes measured using and CTG assay on mock-infected cells.
Figure 6
Figure 6
AntiviralCombi.info database summarizing existing antiviral drug combinations. (A) Developmental phases of combinations are presented in the database. (B) Database summary statistics. (C) An example snapshot of the database showing information on the amodiaquine and clomiphene drug combination.
Figure 7
Figure 7
Synergistic virus- (green) and host- (orange) targeting drug combinations identified in this study. HCV: hepatitis C virus.
See this image and copyright information in PMC

References

    1. DALYs G.B.D., Collaborators H. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1260–1344. doi: 10.1016/S0140-6736(17)32130-X. - DOI - PMC - PubMed
    1. Disease G.B.D., Injury I., Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–1259. doi: 10.1016/S0140-6736(17)32154-2. - DOI - PMC - PubMed
    1. Chaudhuri S., Symons J.A., Deval J. Innovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond. Antivir. Res. 2018;155:76–88. doi: 10.1016/j.antiviral.2018.05.005. - DOI - PMC - PubMed
    1. Andersen P.I., Ianevski A., Lysvand H., Vitkauskiene A., Oksenych V., Bjoras M., Telling K., Lutsar I., Dumpis U., Irie Y., et al. Discovery and development of safe-in-man broad-spectrum antiviral agents. Int. J. Infect. Dis. 2020;93:268–276. doi: 10.1016/j.ijid.2020.02.018. - DOI - PMC - PubMed
    1. Fu Y., Gaelings L., Soderholm S., Belanov S., Nandania J., Nyman T.A., Matikainen S., Anders S., Velagapudi V., Kainov D.E. JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses. Antivir. Res. 2016;133:23–31. doi: 10.1016/j.antiviral.2016.07.008. - DOI - PubMed

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