ArticleThe Journal of biological chemistry2020
Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 162 citations in OpenAlex.
- SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants.Antimicrobial agents and chemotherapy · 2025Trial
- Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1).The Journal of infectious diseases · 2023Trial
- Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial.Intensive care medicine · 2021Trial
- Identification of key metabolic enzymes involved in the activation of obeldesivir and remdesivir to the active triphosphate metabolite.Antimicrobial agents and chemotherapy · 2026Article
- Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases.The Journal of biological chemistry · 2026Article
- The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.bioRxiv : the preprint server for biology · 2026Article
- Copy-back RNA synthesis by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.Science advances · 2026Article
- Polymerase-inhibitor drug synergy and mutational signatures in different epithelial cell models of RSVA and hPIV3 infection.npj antimicrobials and resistance · 2026Article
- Cardiovascular Risks of COVID-19 Therapeutics: Integrated Analysis of FAERS, Electronic Health Records, and Transcriptomics.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Preferential remdesivir triphosphate incorporation by SARS-CoV-2 polymerase is altered to ATP by the S759A mutation.Communications biology · 2026Article
- 1'- and 4'-Cyano Modified Adenosine Analogs Against Prototypic Flavivirus RNA-Dependent RNA Polymerases.Viruses · 2026Article
- Remdesivir in COVID-19: pros and cons.Frontiers in pharmacology · 2026Review
- Structural basis for selective remdesivir incorporation by SARS-CoV-2 polymerase, and S759A resistance.Research square · 2025Article
- Dual-Site Inhibition of SARS-CoV-2 RNA-Dependent RNA Polymerase by Small Molecules Able to Block Viral Replication Identified through a Computer-Aided Drug Discovery Approach.ACS infectious diseases · 2025Article
- Template switching by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir.bioRxiv : the preprint server for biology · 2025Article
- Mechanism of Inhibition of the Active Triphosphate Form of 2'-α-Fluoro,2'-β-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase.ACS infectious diseases · 2025Article
- In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs.Biochemistry and biophysics reports · 2025Article
- A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent.Nucleic acids research · 2025Article
- Mechanistic insights into the activity of SARS-CoV-2 RNA polymerase inhibitors using single-molecule FRET.Nucleic acids research · 2025Article
- From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants.Journal of medicinal chemistry · 2025Article
50 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Remdesivir (RDV) is a direct-acting antiviral agent that is used to treat patients with severe coronavirus disease 2019 (COVID-19). RDV targets the viral RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have previously shown that incorporation of the active triphosphate form of RDV (RDV-TP) at position i causes delayed chain termination at position i + 3. Here we demonstrate that the S861G mutation in RdRp eliminates chain termination, which confirms the existence of a steric clash between Ser-861 and the incorporated RDV-TP. With WT RdRp, increasing concentrations of NTP pools cause a gradual decrease in termination and the resulting read-through increases full-length product formation. Hence, RDV residues could be embedded in copies of the first RNA strand that is later used as a template. We show that the efficiency of incorporation of the complementary UTP opposite template RDV is compromised, providing a second opportunity to inhibit replication. A structural model suggests that RDV, when serving as the template for the incoming UTP, is not properly positioned because of a significant clash with Ala-558. The adjacent Val-557 is in direct contact with the template base, and the V557L mutation is implicated in low-level resistance to RDV. We further show that the V557L mutation in RdRp lowers the nucleotide concentration required to bypass this template-dependent inhibition. The collective data provide strong evidence to show that template-dependent inhibition of SARS-CoV-2 RdRp by RDV is biologically relevant.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.