Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

Abstract

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

Mono- and combinational drug therapies for global viral pandemic preparedness

“…Interestingly, many predicted BCCs contain nucleotide/nucleoside analogs along with inhibitors of pyrimidine/purine biosynthesis, cap analogs, or IFNs, which also target viral RNA synthesis via IFN-induced RNases. Indeed, such combinations showed synergy in experiments performed in our and other laboratories ( Bellobuono et al., 1997 ; Byrn et al., 2015 ; Falloon et al., 2000 ; Herring et al., 2021 ; Ianevski et al., 2021a , 2021b ; Li et al., 2020 , 2022 ; Phillips et al., 2015 ; Pires de Mello et al., 2018 ; Schultz et al., 2022 ; Tong et al., 2018 ; Wedemeyer et al., 2013 ). Thus, our preliminary results suggest that scores could correlate with the antiviral efficacy of BCCs and that some of these combinations could be used as pan- and even cross-virus family .…”

“…Furthermore, many dual drug combinations are now in clinical trials against SARS-CoV-2, HCV, HBV, HSV-1, and other viral infections ( Ianevski et al., 2020b ). In addition, many BCCs have been tested in vitro and in animal models ( Dyall et al., 2018 ; Finch et al., 2021 ; Herring et al., 2021 ; Ianevski et al., 2020c , 2021a , 2021b ) (Li et al.). These and other studies further demonstrate the potential for antiviral combinations for the treatment of emerging and re-emerging viral infections.…”

Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

“…Furthermore, many dual drug combinations are now in clinical trials against SARS-CoV-2, HCV, HBV, HSV-1, and other viral infections [59]. In addition, many BCCs have been tested in vitro and in animal models [27,34,[60][61][62][63]. These and other studies further demonstrate the potential for antiviral combinations for the treatment of emerging and re-emerging viral infections.…”

Broad-Spectrum Antivirals and Antiviral Drug Combinations

“…In this Special Issue, authors report novel, and review known, BSAs and BCCs [8][9][10][11]. Their results indicate that the landscape of BSAs and BCCs activities and virus coverage is vast, and can be further interrogated and expanded.…”

“…Their results indicate that the landscape of BSAs and BCCs activities and virus coverage is vast, and can be further interrogated and expanded. The basic science data generated by these articles unveil new insights into the interactions between virus and host during viral infections and decipher the mechanisms of action of inhibitors and modulators of these interactions [8][9][10][11][12]. This may help us to uncover critical virus-host interactions and the underlying principles, which determine pan-and cross-family activities of BSAs, as well as understand what makes some BCCs act synergistically, something that is still largely unknown in the medical science community.…”