ArticlePLoS biology2024
The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- NS5-targeting nucleoside analogs inhibit dengue virus and other flaviviruses.PLoS pathogens · 2026Article
- Prodrug strategies in developing antiviral nucleoside analogs.RSC medicinal chemistry · 2026Review
- Meeting report: 38th international conference on antiviral research in Las Vegas, United States of America, March 17-21, 2025.Antiviral research · 2025Article
- Comprehensive profiling of the catalytic conformations of human Guanylate kinase.Nature communications · 2025Article
- Structural basis for the substrate specificity of Helix pomatia AMP deaminase and a chimeric ADGF adenosine deaminase.The Journal of biological chemistry · 2025Article
- Derivatives of MOPS: promising scaffolds for SARS coronaviruses Macro domain-targeted inhibition.The FEBS journal · 2025Article
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5'-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with its metabolic activation. Crystal structures of human histidine triad nucleotide binding protein 1, adenosine deaminase-like protein 1, guanylate kinase 1, and nucleoside diphosphate kinase at 2.09, 2.44, 1.76, and 1.9 Å resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug-protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5'-triphosphate assembly line.
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Registered trials
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