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. Thaiss, Matthew B. Frieman () and Sara Cherry ()
Additional contact information
David C. Schultz: University of Pennsylvania
Robert M. Johnson: University of Maryland School of Medicine
Kasirajan Ayyanathan: University of Pennsylvania
Jesse Miller: University of Pennsylvania
Kanupriya Whig: University of Pennsylvania
Brinda Kamalia: University of Pennsylvania
Mark Dittmar: University of Pennsylvania
Stuart Weston: University of Maryland School of Medicine
Holly L. Hammond: University of Maryland School of Medicine
Carly Dillen: University of Maryland School of Medicine
Jeremy Ardanuy: University of Maryland School of Medicine
Louis Taylor: University of Maryland School of Medicine
Jae Seung Lee: University of Pennsylvania
Minghua Li: University of Pennsylvania
Emily Lee: National Institutes of Health
Clarissa Shoffler: University of Pennsylvania
Christopher Petucci: University of Pennsylvania
Samuel Constant: Epithelix
Marc Ferrer: National Institutes of Health
Christoph A. Thaiss: University of Pennsylvania
Matthew B. Frieman: University of Maryland School of Medicine
Sara Cherry: University of Pennsylvania

Nature, 2022, vol. 604, issue 7904, 134-140

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04482-x

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