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

Abstract

Cellular drug response (concentration required for obtaining 50% of a maximum cellular effect, EC₅₀) can be predicted by the intracellular bioavailability (F_ic) and biochemical activity (half-maximal inhibitory concentration, IC₅₀) of drugs. In an ideal model, the cellular negative log of EC₅₀ (pEC₅₀) equals the sum of log F_ic and the negative log of IC₅₀ (pIC₅₀). Here, we measured F_ic’s of remdesivir, favipiravir, and hydroxychloroquine in various cells and calculated their anti-SARS-CoV-2 EC₅₀’s. The predicted EC₅₀’s are close to the observed EC₅₀’s in vitro. When the lung concentrations of antiviral drugs are higher than the predicted EC₅₀’s in alveolar type 2 cells, the antiviral drugs inhibit virus replication in vivo, and vice versa. Overall, our results indicate that both in vitro and in vivo 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.