A new prodrug activation mechanism

Prodrugs have little or no pharmacological activity and require modifications to become active. Most prodrugs contain a chemical group that is removed or modified by the body’s enzymes to lead to the active drug, although a few can be intentionally activated by radiation, electrical stimuli or ultrasounds. However, to date, prodrugs capable of self-activation without enzymes or human intervention remain unknown.
Researchers from the IBS (Protein Dynamics and Flexibility Group) in collaboration with researchers from the IAB (Palencia Group), the EMBL Grenoble (Cusack Group) and the ENS Lyon (Salmon Group) have discovered an enzyme-independent prodrug activation mechanism. By studying boron-based compounds (benzoxaboroles) targeting leucyl-tRNA synthetase (LeuRS), including an antibiotic currently being tested for the treatment of tuberculosis, they discovered that these benzoxaboroles do not bind directly to their drug target LeuRS. Instead, they are prodrugs that are first converted by reaction with adenosine-based biomolecules (e.g. ATP). X-ray crystallography and nuclear magnetic resonance spectroscopy show that these compounds form a ring with the adenosine ribose at physiological concentrations, which can potently bind to the LeuRS target of Mycobacterium tuberculosis.
This novel prodrug activation mechanism represents a new concept in chemistry of therapeutic molecules that could be applied to improve the solubility, permeability and metabolic stability of challenging drugs.

Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase. Hoffmann G, Le Gorrec M, Mestdach E, Cusack S, Salmon L, Jensen MR*, Palencia A*. J .Am. Chem. Soc. (2023)
doi : 10.1021/jacs.2c04808

Contact : Malene R. Jensen (IBS/Protein Dynamics and Flexibility by NMR Group)