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The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution
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The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution
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Journal Article
The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution
2024
Overview
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 N 6 -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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Antiviral Agents - chemistry
/ Antiviral Agents - pharmacology
/ Control
/ COVID-19
/ Enzymes
/ Guanosine - analogs & derivatives
/ HIV
/ Human immunodeficiency virus
/ Humans
/ Kinases
/ Medicine and Health Sciences
/ Nucleoside-diphosphate kinase
/ Nucleoside-Diphosphate Kinase - chemistry
/ Nucleoside-Diphosphate Kinase - genetics
/ Nucleoside-Diphosphate Kinase - metabolism
/ Poisons
/ Proteins
/ Research and Analysis Methods
/ Severe acute respiratory syndrome coronavirus 2
/ Structure-function relationships
/ Testing
/ Toxicity
/ Viruses
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