A Selective SARS-CoV-2 Host-Directed Antiviral Targeting Stress Response to Reactive Oxygen Species

[Image: see text] The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) catalyzed the development of vaccines and antivirals. Clinically approved drugs against SARS-CoV-2 target the virus directly, which makes them susceptible to viral mutations, which in turn can attenuate their antiviral activity. Here we report a host-directed antiviral (HDA), piperlongumine (PL), which exhibits robust antiviral activity as a result of selective induction of reactive oxygen species in infected cells by GSTP1 inhibition. Using a transgenic K18-hACE2 mouse model, we benchmarked PL against plitidepsin, a HDA undergoing phase III clinical trials. We observed that intranasal administration of PL is superior in delaying disease progression and reducing lung inflammation. Importantly, we showed that PL is effective against several variants of concern (VOCs), making it an ideal pan-variant antiviral. PL may display a critical role as an intranasal treatment or prophylaxis against a range of viruses, expanding the arsenal of tools to fight future outbreaks.