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bioRxiv · 10.1101/2024.02.16.580631

The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution

Chazot, A.·Zimberger, C.·Feracci, M.·Moussa, A.·Good, S.·Sommadossi, J.-P.·ALVAREZ, K.·Ferron, F.·Canard, B.
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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 broad spectrum antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with metabolic activation by human ADALP1. Crystal structures of human HINT1, ADALP1, GUK1, and NDPK at 2.09, 2.44, 1.76, and 1.9 [A] 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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Chazot, A., Zimberger, C., Feracci, M., Moussa, A., Good, S., Sommadossi, J.-P., ALVAREZ, K., Ferron, F., Canard, B.. 2024-02-16. The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution. https://doi.org/10.1101/2024.02.16.580631

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