Interferon alpha-based combinations suppress SARS-CoV-2 infection in vitro and in vivo

Abstract

There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggered cell intrinsic and extrinsic antiviral responses and reduced replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung epithelial Calu-3 cells. However, IFNa alone was insufficient to completely abolish SARS-CoV-2 replication. Combinations of IFNa with camostat, remdesivir, EIDD-2801, cycloheximide or convalescent serum showed strong synergy and effectively inhibited SARS-CoV-2 infection. Additionally, we demonstrated synergistic antiviral activity of IFNa2a with pimodivir against influenza A virus (FluAV) infection in human lung epithelial A549 cells, as well as of IFNa2a with lamivudine against human immunodeficiency virus 1 (HIV-1) infection in human TZM-bl cells. Our results indicate that IFNa2a-based combinational therapies help to reduce drug dose and improve efficacy in comparison with monotherapies, making them attractive targets for further pre-clinical and clinical development.

Nafamostat–Interferon-α Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2

“…To test our hypothesis, we first analyzed toxicity and efficacy of Pegasys (pegylated IFNα) and nafamostat, against mCherry-expressing SARS-CoV-2 [20] in human lung epithelial Calu-3 cells using fluorescence and cell viability assay as readouts as described previously [11]. We observed that both Pegasys and nafamostat reduced SARS-CoV-2-mediated mCherry expression and rescued cells from virus-mediated death (Figure 1a).…”

“…However, more targeted studies are needed to support the proposed mechanism of synergy. Our recent transcriptomics analysis revealed that IFNα activates transcription of many genes including endothelial plasminogen activator inhibitor (SERPINE1) in Calu-3 cells and human lung organoids [11]. Serpin E1 inhibits urokinase-type and tissue-type plasminogen activators (uPA and tPA) as well as various membrane-anchored serine proteases including transmembrane protease serine 2 (TMPRSS2) [21].…”

“…The propagation of human non-small-cell lung cancer Calu-3 have been described in our previous studies [11,17].…”

“…Our recent studies have highlighted the synergism of several compounds against SARS-CoV-2 in human lung epithelial Calu-3 cells, with IFNα-remdesivir and camostat-remdesivir combinations having the highest synergy scores [2,10,11]. In these studies, we were also able to show that camostat-remdesivir was effective against SARS-CoV-2 infection in human lung organoids, as well as that IFNα-remdesivir was effective in both human lung organoids and Syrian hamsters [10,11]. Furthermore, other studies have shown that combinations of IFNα with lopinavir-ritonavir-ribavirin as well as nafamostat with favipiravir are effective for treatment of patients infected with SARS-CoV-2 [12,13].…”

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…Synergistic drug pairs that do not involve a polymerase inhibitor have also been identified in Vero E6 cells, including nelfinavir plus amodiaquine ( 71 ), arbidol plus nitazoxanide ( 73 ), nitazoxanide plus emetine ( 73 ), and nelfinavir plus cepharanthine ( 78 ). Additional non-polymerase-targeted pairs found synergistic in Calu3 cells were interferon alpha plus camostat ( 86 ), interferon alpha plus nafamostat ( 96 ), and apilimod plus camostat ( 103 ). Interferon alpha plus nafamostat reduced viral loads in hamsters to a greater extent than the individual component drugs ( 96 ).…”