Discussion
In this work, we show that prophylaxis with tenofovir-based compounds, particularly TDF, might be capable of reducing viral replication during SARS-CoV-2 infection, which in turn might reduce disease severity (and potential mortality). Our findings suggest that this suboptimal clinical effect (i.e. limiting viral growth and subsequent disease severity but not fully blocking viral replication) could arise from suboptimal binding of active tenofovir into the SARS-CoV-2 RNA dependent RNA polymerase. In particular we found in the molecular model that suboptimal tenofovir-RdRp-CoV2 interaction compared to remdesivir, predicting that the ensemble is more sensitive to the phosphate-form intracellular concentration. Thus, matching sufficient intracellular availability of tenofovir-diphostate with SARS-CoV2 tropism [21,26](such as in the respiratory tract [27]) is likely essential in drug-driven containment of viral replication, mirroring what happens during HIV prophylaxis [28].  However, other factors than limited inhibition, including drug-penetration into viral targeted tissues and time-to-treatment relative to exposure are key determinants of infection outcomes.