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Updated: Jul 16, 2025

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Current understanding of nucleoside analogs inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase
Tiantian Xu1,2, Lu Zhang1,2,3
1State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
Abstract:
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.
Insights
Nucleoside analogs show promise in inhibiting SARS-CoV-2 replication by targeting the viral RNA-dependent RNA polymerase (RdRp). This review summarizes experimental findings and molecular mechanisms for developing new antiviral drugs.
Area of Science:
- Virology
- Medicinal Chemistry
- Structural Biology
Background:
- The COVID-19 pandemic necessitates novel antiviral therapeutics targeting SARS-CoV-2.
- The viral RNA-dependent RNA polymerase (RdRp) is crucial for viral replication and a key target for drug development.
- Nucleoside analogs, mimicking natural substrates, are promising inhibitors of SARS-CoV-2 RdRp.
Purpose of the Study:
- To review nucleoside analogs demonstrating experimental inhibition of SARS-CoV-2 RdRp.
- To elucidate the molecular mechanisms of nucleoside analog action against SARS-CoV-2 RdRp.
- To guide the rational design of antiviral medications and research into viral transcription.
Main Methods:
- Literature review of experimental investigations on nucleoside analogs targeting SARS-CoV-2 RdRp.
- Analysis of structural biology and computational research findings.
- Classification of inhibitory mechanisms based on recent studies.
Main Results:
- Compilation of nucleoside analogs with proven inhibitory effects on SARS-CoV-2 RdRp.
- Detailed examination of molecular mechanisms, including structural insights.
- Categorization of inhibition strategies based on experimental and computational data.
Conclusions:
- Nucleoside analogs are effective inhibitors of SARS-CoV-2 RdRp.
- Understanding molecular mechanisms is key to optimizing antiviral drug design.
- This review provides a foundation for future research in antiviral therapies and viral mechanisms.
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