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The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.

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.

SUBMITTER: Chazot A

PROVIDER: S-EPMC11349198 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.

Chazot Aurélie A Zimberger Claire C Feracci Mikael M Moussa Adel A Good Steven S Sommadossi Jean-Pierre JP Alvarez Karine K Ferron François F Canard Bruno B

PLoS biology 20240827 8

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. Cry ...[more]

PMID: 39190717

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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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