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

Abstract

The SARS-CoV-2 virus has infected more than 261 million people and led to more than 5 million deaths in the last year and a half1 (WHO.org). SARS-CoV-2-infected individuals typically develop mild to severe flu-like symptoms, while infection of a subset of individuals leads to severe to fatal clinical outcomes2. While 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 and we screened ~18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst 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.