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

Abstract

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

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

“…Similarly, other IFNα-induced ISGs, together with inhibitors, can synergistically target the same processes, which play a critical role in viral replication. This is in agreement with previous studies [65][66][67].…”

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 ( 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 [27,34,60-63]. These and other studies further demonstrate the potential for antiviral combinations for the treatment of emerging and re-emerging viral infections.…”