Recent Development of Aminoacyl-tRNA Synthetase Inhibitors for Human Diseases: A Future Perspective

Figure 1. Two-step catalytic reaction of aminoacyl-tRNA synthetases (ARSs). ARSs use an amino acid (aa), ATP, and tRNA as substrates to produce an aminoacylated tRNA (tRNA-aa) that leads to protein synthesis in the ribosome.

Figure 2. AN2690-tRNALeu adduct via the oxaborole tRNA-trapping (OBORT) mechanism.

Figure 3. Benzoxaborole PT638 is reduced by a nitroreductase to PT662.

Figure 4. Development of GSK656 through hit-to-lead optimization.

Figure 5. Optimization of cladosporin to improve pharmacokinetic properties [26,28].

Figure 6. Optimization of cladosporin by replacing the core with a chromone scaffold.

Figure 7. Binding modes of cladosporin and 20 to Pf LysRS1. Pf LysRS1:Lys:20 showing the binding mode of 20 (C atoms, gold) bound to the ATP site of Pf LysRS1 (PDB ID code 6AGT) superimposed upon Pf LysRS1:Lys:cladosporin (cladosporin C atoms, slate; PDB ID code 4PG3). The image was reproduced from reference 29 by Baragaña et al. and adapted for repurposing.

Figure 8. Optimization of borrelidin selectivity for Plasmodium falciparum over human threonyl-tRNA synthetase (ThrRS).

Figure 9. YH16899, a protein–protein interaction inhibitor of LysRS and 67-kDa laminin receptor (67LR).

Figure 10. Antifibrotic prolyl-tRNA synthetase (ProRS) inhibitors halofuginone and T-3833261.

Figure 11. Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 lacking exon 2 (AIMP2-DX2) interaction inhibitors.

Figure 12. BRD7929, a potent inhibitor of Pf PheRS for malaria.