Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2

David C. Schultz, Robert M. Johnson, Kasirajan Ayyanathan, Jesse Miller, Kanupriya Whig, Brinda Kamalia, Mark Dittmar, Stuart Weston, Holly L. Hammond, Carly Dillen, Jeremy Ardanuy, Louis Taylor, Jae Seung Lee, Minghua Li, Emily Lee, Clarissa Shoffler, Christopher Petucci, Samuel Constant, Marc Ferrer, Christoph A. ThaissMatthew B. Frieman, Sara Cherry

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half1 (https://www.who.org/). Individuals with SARS-CoV-2 infection typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes2. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. 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. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward.

Original languageEnglish (US)
Pages (from-to)134-140
Number of pages7
JournalNature
Volume604
Issue number7904
DOIs
StatePublished - Apr 7 2022
Externally publishedYes

ASJC Scopus subject areas

  • General

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