Adenosine-dependent activation mechanism of prodrugs targeting an aminoacyl-tRNA synthetase

Guillaume Hoffmann (1) , Madalen Le Gorrec (1) , Emeline Mestdach (2) , Stephen Cusack (3) , Loïc Salmon (2) , Malene Ringkjøbing Jensen (4) , Andrés Palencia (1)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 CRMN - Centre de RMN à très hauts champs de Lyon
3 EMBL - European Molecular Biology Laboratory [Grenoble]
4 IBS - UMR 5075 - Institut de biologie structurale

Prodrugs have little or no pharmacological activity and are converted to active drugs in the body by enzymes, metabolic reactions, or through human-controlled actions. However, prodrugs promoting their chemical bioconversion without any of these processes have not been reported before. Here, we present an enzyme-independent prodrug activation mechanism by boron-based compounds (benzoxaboroles) targeting leucyl-tRNA synthetase (LeuRS), including an antibiotic that recently has completed phase II clinical trials to cure tuberculosis. We combine nuclear magnetic resonance spectroscopy and X-ray crystallography with isothermal titration calorimetry to show that these benzoxaboroles do not bind directly to their drug target LeuRS, instead they are prodrugs that activate their bioconversion by forming a highly specific and reversible LeuRS inhibition adduct with ATP, AMP, or the terminal adenosine of the tRNALeu. We demonstrate how the oxaborole group of the prodrugs cyclizes with the adenosine ribose at physiological concentrations to form the active molecule. This bioconversion mechanism explains the remarkably good druglike properties of benzoxaboroles showing efficacy against radically different human pathogens and fully explains the mechanism of action of these compounds. Thus, this adenosine-dependent activation mechanism represents a novel concept in prodrug chemistry that can be applied to improve the solubility, permeability and metabolic stability of challenging drugs.

Domaines: Sciences du Vivant [q-bio]

Guillaume Hoffmann, Madalen Le Gorrec, Emeline Mestdach, Stephen Cusack, Loïc Salmon, et al.. Adenosine-dependent activation mechanism of prodrugs targeting an aminoacyl-tRNA synthetase. Journal of the American Chemical Society, 2023, 145 (2), pp.800-810. ⟨10.1021/jacs.2c04808⟩. ⟨hal-04025430⟩