Repurposing dyphylline as a pan-coronavirus antiviral therapy

Background: In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human coronaviruses (HCoVs), mainly from the alpha-CoV and beta-CoV genera, have evolved to be highly pathogenic, such as SARS-CoV-2 causing the COVID-19 pandemic. These coronaviruses carry functional enzymes necessary for the virus life cycle, which represent attractive antiviral targets. Methods & Results: We aimed to therapeutically target the main protease (Mpro) of HCoV-NL63 and HCoV-229E (from alpha-CoV genus) and HCoV-OC43 and SARS-CoV-2 (from beta-CoV genus). Through virtual screening, we identified an FDA-approved drug dyphylline, a xanthine derivate, that binds to the catalytic dyad residues; histidine and cystine of the Mpro structures. Importantly, dyphylline dose-dependently inhibited the viral replication in cell culture models infected with the viruses. Conclusion: Our findings support the repurposing of dyphylline as a pan-coronavirus antiviral agent.