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. 2022 Aug 25;14(9):1866.
doi: 10.3390/v14091866.

Novel Synergistic Anti-Enteroviral Drug Combinations

Aleksandr Ianevski  1 , Eva Zusinaite  2 , Tanel Tenson  2 , Valentyn Oksenych  1 , Wei Wang  1 , Jan Egil Afset  1   3 , Magnar Bjørås  1 , Denis E Kainov  1   2   4
Affiliations

Novel Synergistic Anti-Enteroviral Drug Combinations

Aleksandr Ianevski et al. Viruses. .

Abstract

Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir-vemurafenib, vemurafenib-pleconaril and rupintrivir-pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections.

Keywords: antiviral drug combination; antiviral strategy; broad-spectrum antiviral agent; echovirus; enterovirus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Anti-EV1 activity of 239 broad-spectrum antivirals (BSAs) in A549 cells. (a) Structure–antiviral activity relation of BSAs. A549 cells were treated with increasing concentrations of a compound and infected with the EV1 (moi, 0.1). After 48 h, the viability of the cells was determined using the CellTiter-Glo (CTG) assay. The anti-EV1 activity of the compounds was quantified using the drug sensitivity scores (DSS) and shown as bubbles. Bubble size corresponds to compounds DSSs. The compounds were clustered based on their structural similarity calculated by ECPF4 fingerprints and visualized using the D3 JavaScript library. (b) Validation of anti-EV1 activity of hit compounds in A549 cells. A549 cells were treated with increasing concentrations of a compound and infected with the EV1 (moi, 0.1: blue) or mock (red). After 48 h, the viability of the cells was determined using the CTG assay. Mean ± SD; n = 3. Plots for 6 most effective BSAs are shown. (c) Table showing selectivity indexes (SI = CC50/EC50) and ΔDSS for selected BSAs.
Figure 2
Figure 2
Anti-EV1 activity of BSA-containing combinations (BCCs). (a) The interaction landscape of the rupintrivir–pleconaril combination was measured using the CellTiter-Glo (CTG) assay on EV1-infected cells. (b) The interaction landscape of the rupintrivir–pleconaril combination measured using the CTG assay on mock-infected cells. (c) Synergy interaction landscape for selectivity (Selectivity=Efficacy-(100-Toxicity)) of the drug combination. (d) ZIP synergy scores calculated for the most synergistic areas (MSA) of interaction landscapes for selectivity obtained for rupintrivir-containing drug combinations on A549 cells. (e) Heatmap showing ZIP synergy scores calculated for the most synergistic areas (MSA) of interaction landscapes for selectivity obtained for 3 BSA combinations on A549 and RPE cells. (f) The effects of different concentrations of rupintrivir, pleconaril, vemurafenib and their combinations on replication of EV1 in A549 and RPE cells measured by plaque reduction assay.
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References

    1. Wang J., Hu Y., Zheng M. Enterovirus A71 antivirals: Past, present, and future. Acta Pharm. Sin. B. 2022;12:1542–1566. doi: 10.1016/j.apsb.2021.08.017. - DOI - PMC - PubMed
    1. Abzug M.J., Cloud G., Bradley J., Sanchez P.J., Romero J., Powell D., Lepow M., Mani C., Capparelli E.V., Blount S., et al. Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis. Pediatr. Infect. Dis. J. 2003;22:335–341. doi: 10.1097/01.inf.0000059765.92623.70. - DOI - PubMed
    1. Abzug M.J., Michaels M.G., Wald E., Jacobs R.F., Romero J.R., Sanchez P.J., Wilson G., Krogstad P., Storch G.A., Lawrence R., et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates with Enterovirus Sepsis. J. Pediatr. Infect. Dis. Soc. 2016;5:53–62. doi: 10.1093/jpids/piv015. - DOI - PMC - PubMed
    1. Hayden F.G., Herrington D.T., Coats T.L., Kim K., Cooper E.C., Villano S.A., Liu S., Hudson S., Pevear D.C., Collett M., et al. Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: Results of 2 double-blind, randomized, placebo-controlled trials. Clin. Infect. Dis. 2003;36:1523–1532. doi: 10.1086/375069. - DOI - PMC - PubMed
    1. Hayden F.G., Turner R.B., Gwaltney J.M., Chi-Burris K., Gersten M., Hsyu P., Patick A.K., Smith G.J., 3rd, Zalman L.S. Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers. Antimicrob. Agents Chemother. 2003;47:3907–3916. doi: 10.1128/AAC.47.12.3907-3916.2003. - DOI - PMC - PubMed

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