ArticleAntimicrobial agents and chemotherapy2021
Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells.
Article in Antimicrobial agents and chemotherapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 61 citations in OpenAlex.
- Pharmacokinetics, safety, and tolerability of inhaled remdesivir in healthy participants.Clinical and translational science · 2023Trial
- Identification of key metabolic enzymes involved in the activation of obeldesivir and remdesivir to the active triphosphate metabolite.Antimicrobial agents and chemotherapy · 2026Article
- Remdesivir as a potent antiviral against prototype and current epidemic Oropouche virus strains (BeAn19991 and PE-IAM4637).Virus research · 2026Article
- Article
- A dual-reporter HCoV-OC43 for coronavirus biology and countermeasure development.Antiviral research · 2025Article
- Characterization of Drug-Drug Interactions for Remdesivir, an Intravenous Antiviral for SARS-CoV-2, in Healthy Participants.Clinical and translational science · 2025Article
- A Novel HPLC-MS/MS Method for the Intracellular Quantification of the Active Triphosphate Metabolite of Remdesivir: GS-443902.Journal of xenobiotics · 2025Article
- Carboxylesterase Factors Influencing the Therapeutic Activity of Common Antiviral Medications Used for SARS-CoV-2 Infection.Pharmaceutics · 2025Review
- Article
- Thio-ProTide strategy: A novel HActa pharmaceutica Sinica. B · 2024Article
- The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.PLoS biology · 2024Article
- Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells.RSC medicinal chemistry · 2024Article
- Development of robust antiviral assays using relevant apical-out human airway organoids.bioRxiv : the preprint server for biology · 2024Article
- Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect.Acta pharmaceutica Sinica. B · 2024Article
- Differential Bioactivation Profiles of Different GS-441524 Prodrugs in Cell and Mouse Models: ProTide Prodrugs with High Cell Permeability and Susceptibility to Cathepsin A Are More Efficient in Delivering Antiviral Active Metabolites to the Lung.Journal of medicinal chemistry · 2024Article
- Regulation of carboxylesterases and its impact on pharmacokinetics and pharmacodynamics: an up-to-date review.Expert opinion on drug metabolism & toxicology · 2024Review
- Article
- The Many Faces of Histidine Triad Nucleotide Binding Protein 1 (HINT1).ACS pharmacology & translational science · 2023Review
- Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys.Journal of medicinal chemistry · 2023Article
- Multi-omics for COVID-19: driving development of therapeutics and vaccines.National science review · 2023Review
Corrections and comments
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Authors and funding
24 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Remdesivir (RDV; GS-5734, Veklury), the first FDA-approved antiviral to treat COVID-19, is a single-diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which, in turn, acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (i) bioinformatic analysis of nucleoside/nucleotide metabolic enzyme mRNA expression using public human tissue and lung single-cell bulk mRNA sequence (RNA-seq) data sets, (ii) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells, (iii) biochemical studies on the catalytic rate of key enzymes, (iv) effects of specific enzyme inhibitors on the GS-443902 formation, and (v) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate MetX, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19 but also enable efficient intracellular metabolism of RDV and its MetX to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.
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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.