Our docking approach is the first to include template-nascent RNA in the ensemble and further improves previous work [33] by using cryo-EM structures instead of homology and by more extensive sampling of the ligand poses using volunteer distributed computations. Consistent with our findings, tenofovir-diphosphate has been shown to permanently terminate polymerase extension of nascent RNA when using recombinant RdRp-CoV2 [34]. However, infusion of tenofovir in Vero cell cultures did not inhibit replication of SARS-CoV-2 [13,35], while the use of 3-90 μM of its prodrug TDF yielded a 15-fold reduction of viral genome release as explained before [35] . Further, the use of TDF/FTC for treating SARS-CoV-2 infected ferrets led to better clinical scores and lower virus titers in nasal washes compared to a placebo [36]. Worth noting, the prodrug TDF, formulated to increase tenofovir limited bioavailability [37], is known to diffuse passively across cellular membranes [38,39] and further activate intracellularly, as opposed to tenofovir which requires active transportation for intake before activation [40,41]. Indeed, higher levels of active metabolite after exposure to TDF versus tenofovir has been consistently reported in several cell types [28,42,43]. In contrast, the prodrug TAF was formulated to reduce drug-adverse events observed for TDF (which distributes body-wide) by being highly HIV-target-cell specific. TAF is well known to selectively activate and present preferential distribution in lymphatic tissues [26]