Experimental validation of computationally prioritized bisphosphonates reveals no direct in vitro antiviral activity against SARS-CoV-2
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It is essential to experimentally evaluate antiviral efficacy predicted by molecular docking and related in silico approaches, which this study achieves for three bisphosphonates (alendronate, minodronate, zoledronate) and treprostinil, identified as potential antiviral therapies in our previous work. These investigational compounds had no detectable cytotoxicity at concentrations up to 25µM in Vero E6 cells but also failed to show any antiviral effect against the PQ.8.1 isolate of SARS-CoV-2, when compared to control drugs (ensitrelvir, nirmatrelvir and remdesivir). It appears that for bisphosphonates, any protective effect is likely due to other virus- or host-mediated mechanisms of action. This study demonstrates the importance of iterating between theoretical hypotheses and experiments to elucidate underlying mechanisms at play.
Significance statement
Repurposed drugs could have unexpected antiviral activities of their own as we previously demonstrated with fluvoxamine, therefore, experimentally ruling this out for bisphosphonates is important. Likely mechanisms of action could involve cathepsin and RdRp, then this could have wide implications beyond SARS-CoV-2. If bisphosphonates provide partial protection against COVID-19, then current and future vaccine and drug studies should take this into account in their design.
