Chain Termination Effects of Chemically Modified Nucleoside Analogs on SARS-CoV-2 RNA Polymerase

In the current scenario, the available drugs for SARS-CoV-2 are extremely limited. Among the potential therapeutic targets, the RNA-dependent RNA polymerase (RdRp) complex, essential for viral replication and transcription, presents a promising focal point for drug design. This study explores the mechanistic effects of chemically modified nucleoside analogs on the activity of SARS-CoV-2 RdRp and the subsequent chain termination of viral RNA synthesis. We investigate a range of modifications, including 2’-fluoro (2’-F), 2’-O-methyl, and 3’-deoxy substitutions on the sugar as well as base component changes, to ascertain their incorporation by RdRp and resistance to proofreading by the nsp14/nsp10 exonuclease complex. Through a combination of enzymatic experiments, we elucidate the influence of these modifications on RdRp efficiency. Our findings demonstrate that 2’-OMe-NTP, 3’-dNTP, 6-Aza-UTP can enhance the likelihood of chain termination, offering insights into the design of nucleoside analogs with potent antiviral activities. The study’s comprehensive analysis not only furthers our understanding of SARS-CoV-2’s molecular biology but also contributes to the strategic development of antiviral agents with the potential to combat the current pandemic and prepare for future coronavirus outbreaks.