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

Aurelie Chazot (1) , Claire Zimberger (1) , Mikael Feracci (1) , Adel Moussa (2) , Steven Good (2) , Jean-Pierre Sommadossi (2) , Karine Alvarez (1) , Francois Ferron (3, 1) , Bruno Canard (1)

1 AFMB - Architecture et fonction des macromolécules biologiques
2 Atea Pharmaceuticals
3 European Virus Bioinformatics Center [Jena]

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.

Domaines: Biochimie, Biologie Moléculaire; Biophysique; Biologie structurale [q-bio.BM]; Bio-Informatique, Biologie Systémique [q-bio.QM]

Aurelie Chazot, Claire Zimberger, Mikael Feracci, Adel Moussa, Steven Good, et al.. The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution. 2024. ⟨hal-04474786⟩