Aminoacyl-tRNA synthetases as drug targets

Abstract

Aminoacyl-tRNA synthetases (AARSs) have been considered very attractive drug-targets for decades. This interest probably emerged with the identification of differences in AARSs between prokaryotic and eukaryotic species, which provided a rationale for the development of antimicrobials targeting bacterial AARSs with minimal effect on the homologous human AARSs. Today we know that AARSs are not only attractive, but also valid drug targets as they are housekeeping proteins that: (i) play a fundamental role in protein translation by charging the corresponding amino acid to its cognate tRNA and preventing mistranslation mistakes [1], a critical process during fast growing conditions of microbes; and (ii) present significant differences between microbes and humans that can be used for drug development [2]. Together with the vast amount of available data on both pathogenic and mammalian AARSs, it is expected that, in the future, the numerous reported inhibitors of AARSs will provide the basis to develop new therapeutics for the treatment of human diseases. In this chapter, a detailed summary on the state-of-the-art in drug discovery and drug development for each aminoacyl-tRNA synthetase will be presented.

Keywords: Analogues of amino acids+ATP as inhibitors of AARSs; Differences between AARSs of pathogens and their human counterparts; Inhibitors of the editing site of AARSs; Inhibitors of the synthetic site of AARSs; Natural products as inhibitors of AARSs; Protein synthesis inhibitors; Selective inhibitors; Structure-based drug design; Therapeutic applications involving either the targeting or the use of human AARSs; Therapeutic targets in infectious diseases.