Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

The COVID-19 pandemic has unveiled an urgent need for new anti-virals to control emerging infectious diseases and potential future pandemics. Classic anti-virals are currently designed to directly interfere with pathogens. However, anti-virals are often insufficient to rapidly clear infections in the absence of an effective immune response. Immunotherapy could complement the use of anti-virals, however its application to infectious diseases remains largely unexplored. In this work, we found that the anti-viral drug remdesivir has previously unknown immunomodulatory properties which contribute to its therapeutic effect against SARS-CoV-2. These properties are due to remdesivir metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist, a function that is distinct from its intrinsic anti-viral activity. Our findings support a new rationale for the design of next-generation anti-viral agents with dual – immunomodulatory and intrinsic - anti-viral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics. C57Bl/6J mice treated IP with REM (10mg/kg) before infection with 10^5 PFUs of mouse-adapted SARS-CoV-2 (MA30) under BSL3 conditions. Treatment continued for the duration of the experiment. Mouse lungs were collected, fixed and used for RNA isolation to study differentially expressed genes in response to the infection/treatment.