Current understanding of nucleoside analogs inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase

Since the outbreak of the COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) has become a main target for antiviral therapeutics due to its essential role in viral replication and transcription. Thus, nucleoside analogs structurally resemble the natural RdRp substrate and hold great potential as inhibitors. Until now, extensive experimental investigations have been performed to explore nucleoside analogs to inhibit the RdRp, and concerted efforts have been made to elucidate the underlying molecular mechanisms further. This review begins by discussing the nucleoside analogs that have demonstrated inhibition in the experiments. Second, we examine the current understanding of the molecular mechanisms underlying the action of nucleoside analogs on the SARS-CoV-2 RdRp. Recent findings in structural biology and computational research are presented through the classification of inhibitory mechanisms. This review summarizes previous experimental findings and mechanistic investigations of nucleoside analogs inhibiting SARS-CoV-2 RdRp. It would guide the rational design of antiviral medications and research into viral transcriptional mechanisms.