Identification and assessment of fda-approved drugs for repurposing as single and combination therapies against sars-cov-2 infection

ABSTRACT

Rationale SARS-CoV-2 is a novel β-coronavirus that causes a severe disease (COVID-19) in humans. Currently, approved antivirals only provide modest benefits to critically ill patients, require intravenous administration, and are in limited supply. Methods: To address the urgent need for new therapeutics, we performed a computational screen using the freely available platform, mediKanren, to identify a list of 120 FDA-approved drugs with purported activity against SARS-CoV-2. To test these compounds in vitro, we developed a mid-throughput assay based on immunohistochemistry compatible with a 96-well microplate to quantifying the antiviral activity of these compounds against virulent SARS-CoV-2 in the Vero E6 cell line. Results: Of the 120 FDA-approved compounds tested, we identified 11 candidates with potent anti-viral activity. Follow up testing showed all but one of these candidates were equally effective against the seasonal coronavirus, OC-43, and five of these candidates were effective at stopping viral propagation when given 24 hours post infection. Using this same assay to test across a range of doses, we determined the dose-response curves for our 11 best compounds. Based on the predicted efficacy of each drug, we then screened for synergy between all pair-wise combinations of our top hits. We found that the combination of remdesivir with another top candidate, DL-alpha-tocopherol polyethylene glycol succinate (TPGS), was nearly ten times more potent than either drug alone. These results were validated by performing curve-shift analysis, which identified another six drugs that combine with remdesivir in an additive fashion. Response-surface analysis revealed that an equipotent mixture of TPGS and remdesivir yielded maximum synergy, but the potency of both drugs can be significantly enhanced by combining one drug with as little as 10% of the dose of the other drug. Finally, these findings were validated in the Calu 3 cell line. Conclusions: In addition to identifying eleven FDA-approved drugs with antiviral activity against SARS-CoV-2, these results are significant given that cheap, widely available drugs can markedly improve the potency of and protect against resistance to the current standard of care for COVID-19.