Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection
Schultz, D.; Johnson, R.; Ayyanathan, K.; Miller, J.; Whig, K.; Kamalia, B.; Dittmar, M.; Weston, S.; Hammond, H.; Dillen, C.; Castellana, L.; Lee, J. S.; Li, M.; Lee, E. M.; Constant, S.; Ferrer, M.; Thaiss, C.; Frieman, M.; Cherry, S.
Show abstract
The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only [~]90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened [~]18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.
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