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.