Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection.

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.

• Authors: David C Schultz, Robert M Johnson, Kasirajan Ayyanathan, Jesse Miller, Kanupriya Whig, Brinda Kamalia, Mark Dittmar, Stuart Weston, Holly L Hammond, Carly Dillen, Lauren Castellana, Jae Seung Lee, Minghua Li, Emily Lee, Samuel Constant, Marc Ferrer, Christoph A Thaiss, Matthew B Frieman, Sara Cherry
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Jun 24 2021) United States
• PMID: 34189531 (Publication Type: Preprint)