The Strand-biased Transcription of SARS-CoV-2 and Unbalanced Inhibition by Remdesivir

Zhao, Yan; Sun, Jing; Li, Yunfei; Li, Zhengxuan; Xie, Yu; Feng, Ruoqing; Zhao, Jincun; Hu, Yuhui

SARS-CoV-2, a positive single-stranded RNA virus, causes the COVID-19 pandemic. During the viral replication and transcription, the RNA dependent RNA polymerase (RdRp) “jumps” along the genome template, resulting in discontinuous negative-stranded transcripts. Although the sense-mRNA architectures of SARS-CoV-2 were reported, its negative strand was unexplored. Here, we deeply sequenced both strands of RNA and found SARS-CoV-2 transcription is strongly biased to form the sense strand with variable transcription efficiency for different genes. During negative strand synthesis, numerous non-canonical fusion transcripts are also formed, driven by 3-15 nt sequence homology scattered along the genome but more prone to be inhibited by SARS-CoV-2 RNA polymerase inhibitor Remdesivir. The drug also represses more of the negative than the positive strand synthesis as supported by a mathematic simulation model and experimental quantifications. Overall, this study opens new sights into SARS-CoV-2 biogenesis and may facilitate the anti-viral vaccine development and drug design.