Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics. Adenosine analogs predicted to bind to the Adenosine A2A Receptor (A2AR) are endowed with immunomodulatory properties. These properties contribute to their antiviral function and are distinct from the intrinsic antiviral activity of these compounds.Computational modeling and molecular docking shows that remdesivir metabolite GS-441524 is predicted to bind to A2AR.Remdesivir and GS-441524 antagonize A2AR activation and downstream immunological effects in vitro and in vivo.A non-antiviral A2AR antagonist promotes T-cell infiltration and viral clearance in mice infected with SARS-CoV-2.Remdesivir has immunomodulatory effects analogous to an A2AR antagonist in promoting antiviral immune responses. Adenosine analogs predicted to bind to the Adenosine A2A Receptor (A2AR) are endowed with immunomodulatory properties. These properties contribute to their antiviral function and are distinct from the intrinsic antiviral activity of these compounds.