Scientists discover a new prodrug that self-activates with biomolecules in the body


Scientists led by the Institute for Advanced Biosciences (IAB, INSERM, CNRS, UGA) and the Institute of Structural Biology (IBS, CNRS, CEA, UGA) in Grenoble, have discovered a novel prodrug mechanism that allows drug activation without enzymes or human participation, using the ESRF structural biology beamlines. The results are published in the Journal Of The American Chemical Society (JACS).

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A prodrug is a medication or compound that is biologically inactive until it is metabolized into its active form. This means that the prodrug must be converted by enzymes in the body or human controlled-action before it can exert its therapeutic effect. Prodrugs can hence be used to improve drugs’ solubility, stability, or targeted delivery to a specific area of the body, where the active drug would carry out its activity.

Now scientists led by Andrés Palencia at the IAB and Malene Jensen at the IBS in Grenoble have discovered a prodrug that self-activates without enzymes or human action.

The new prodrugs belong to a class of compounds called benzoxaboroles. Instead of binding directly to the target, a key protein for protein synthesis named leucyl-tRNA synthetase (LeuRS), it reacts with adenosine-based biomolecules in the body, like ATP, to become active. This process allows the prodrug to target LeuRS thereby inhibiting protein synthesis in the pathogen and so allowing the treatment of tuberculosis.

The researchers combined X-ray crystallography at the ESRF with nuclear magnetic resonance spectroscopy to reveal how the prodrug cyclizes with the adenosine ribose at physiological concentrations to form a covalent adduct, which potently binds to the M. tuberculosis LeuRS target. “The work at the ESRF has been fundamental in this study, as it has helped to determine the structures of the prodrug bound to the target at atomic resolution (1.1 Å) ”, explains Palencia.


New mechanism for self-activation of a prodrug. When taken orally, the prodrug spontaneously forms a cycle with the adenosine-based biomolecules present in the extracellular body fluids, which facilitates intracellular permeability through the various membranes of the host and the pathogen, the drug transport, and provides stability against metabolic degradation. One of the two adducts is the active molecule which inhibits the LeuRS target of the pathogen M. tuberculosis.

CNT=Concentrated Nucleoside Transporters; ENT=Balanced Nucleoside Transporters. Credits: A. Palencia and M. Jensen.

The scientific and pharmaceutical community has focused on these compounds for the treatment of pulmonary tuberculosis. Clinical trials are advancing at phase 3 thanks to successful results in phase 2. “The trials are showing that this prodrug works, with no serious side effects, for cases of tuberculosis where first-line defence antibiotics do not work due to drug resistance,”, explains Palencia. And he adds: “But no one knew how this molecule was forming the active drug with adenosine-based biomolecules. We have just proven this antibiotic is a prodrug, and to our knowledge, the first one that self-activates with adenosines”.

The prodrug is taken orally and it is expected that upon its contact with saliva, where ATP levels are high, a rapid bioconversion of the prodrug with physiological molecules in the body will take place. It presumably facilitates drug solubility and permeability through different cell membranes (humans and pathogens), provides stability towards metabolic pathways, and minimises undesirable toxicity effects due to the reversibility of the prodrug adducts.

More generally, this prodrug activation mechanism represents a novel concept for prodrug chemistry that could be applied for the improvement of solubility, permeability and metabolic stability of other challenging drugs.



Hoffmann, G. et al, J. Am. Chem. Soc. 2023. Publication Date: January 4, 2023.

Top image: The team at the ESRF. Credits: C. Argoud