TY - JOUR
T1 - Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2
AU - Schultz, David C.
AU - Johnson, Robert M.
AU - Ayyanathan, Kasirajan
AU - Miller, Jesse
AU - Whig, Kanupriya
AU - Kamalia, Brinda
AU - Dittmar, Mark
AU - Weston, Stuart
AU - Hammond, Holly L.
AU - Dillen, Carly
AU - Ardanuy, Jeremy
AU - Taylor, Louis
AU - Lee, Jae Seung
AU - Li, Minghua
AU - Lee, Emily
AU - Shoffler, Clarissa
AU - Petucci, Christopher
AU - Constant, Samuel
AU - Ferrer, Marc
AU - Thaiss, Christoph A.
AU - Frieman, Matthew B.
AU - Cherry, Sara
N1 - Funding Information:
We thank members of the Cherry, Lynch, Frieman and Penn Center for Precision Medicine for advice and discussion; R. Perera for viral preparations; D. Nguyen for his data analysis and all members of the High-Throughput Screening Core at University of Pennsylvania for reagents and technical support; the Penn Metabolomics Core in the Cardiovascular Institute for liquid chromatography–mass spectrometry quantitation of nucleotides; S. Weiss and Y. Li for sharing SARS-related coronavirus 2, isolate USA-WA1/2020; A. Pekosz for SARS-CoV-2 variants (Alpha, Beta, Gamma and Delta); X. Hu, R. Eastman, M. Hall and members of NCATS Compound Management for assembly and preparation of the NCATS compound collections; and CALIBR for providing the ReFrame library and validation plates. This work was supported by grants from the National Institutes of Health to S. Cherry (R01AI074951, R01AI122749, 1R21AI151882 and R01AI140539), as well as funding from the Penn Center for Precision Medicine, Mercatus and the Bill and Melinda Gates Foundation (INV-018479). S. Cherry is a recipient of the Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award, the Deans Innovation Fund as well as Linda and Laddy Montague. Work at the NCATS was funded by the by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (ZIA Project #TR000414-01). M.B.F., R.M.J., H.L.H. and S.W. are supported by funding from Bill and Melinda Gates Foundation (INV-016638), NIH R21AI158134, NIH R21AI153480 and HHS/BARDA ASPR-20-01495.
Funding Information:
We thank members of the Cherry, Lynch, Frieman and Penn Center for Precision Medicine for advice and discussion; R. Perera for viral preparations; D. Nguyen for his data analysis and all members of the High-Throughput Screening Core at University of Pennsylvania for reagents and technical support; the Penn Metabolomics Core in the Cardiovascular Institute for liquid chromatography–mass spectrometry quantitation of nucleotides; S. Weiss and Y. Li for sharing SARS-related coronavirus 2, isolate USA-WA1/2020; A. Pekosz for SARS-CoV-2 variants (Alpha, Beta, Gamma and Delta); X. Hu, R. Eastman, M. Hall and members of NCATS Compound Management for assembly and preparation of the NCATS compound collections; and CALIBR for providing the ReFrame library and validation plates. This work was supported by grants from the National Institutes of Health to S. Cherry (R01AI074951, R01AI122749, 1R21AI151882 and R01AI140539), as well as funding from the Penn Center for Precision Medicine, Mercatus and the Bill and Melinda Gates Foundation (INV-018479). S. Cherry is a recipient of the Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award, the Deans Innovation Fund as well as Linda and Laddy Montague. Work at the NCATS was funded by the by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (ZIA Project #TR000414-01). M.B.F., R.M.J., H.L.H. and S.W. are supported by funding from Bill and Melinda Gates Foundation (INV-016638), NIH R21AI158134, NIH R21AI153480 and HHS/BARDA ASPR-20-01495.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-022-04482-x
DO - 10.1038/s41586-022-04482-x
M3 - Article
C2 - 35130559
AN - SCOPUS:85126243590
SN - 0028-0836
VL - 604
SP - 134
EP - 140
JO - Nature
JF - Nature
IS - 7904
ER -