Predicting In Vitro and In Vivo Anti-SARS-CoV-2 Activities of Antivirals by Intracellular Bioavailability and Biochemical Activity.

Cellular drug response (concentration required for obtaining 50% of a maximum cellular effect, EC) can be predicted by the intracellular bioavailability ( ) and biochemical activity (half-maximal inhibitory concentration, IC) of drugs. In an ideal model, the cellular negative log of EC (pEC) equals the sum of log and the negative log of IC (pIC). Here, we measured 's of remdesivir, favipiravir, and hydroxychloroquine in various cells and calculated their anti-SARS-CoV-2 EC's. The predicted EC's are close to the observed EC's . When the lung concentrations of antiviral drugs are higher than the predicted EC's in alveolar type 2 cells, the antiviral drugs inhibit virus replication , and vice versa. Overall, our results indicate that both and antiviral activities of drugs can be predicted by their intracellular bioavailability and biochemical activity without using virus. This virus-free strategy can help medicinal chemists and pharmacologists to screen antivirals during early drug discovery, especially for researchers who are not able to work in the high-level biosafety lab.