Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

Abstract

Edited by Karin Musier-Forsyth Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3 ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or highthroughput screening as antibiotics and anti-parasitic therapeutics.

Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase inMycobacterium tuberculosis

“…Aminoacyl-tRNA synthetases (aaRSs), a family of ~20 essential enzymes, ligate amino acids to the corresponding tRNAs that decode messenger RNA to produce protein at the translating macromolecular ribosome (2). Inhibition of bacterial aaRS blocks the translation and ultimately shuts down protein synthesis, which is crucial for pathogens to survive in host or inside host cells (3,4). Between a bacterial aaRS protein and its human counterpart, either the large sequence difference or small variation of key residues in the catalytic core explains the high selectivity of successful and promising aaRS inhibitor drugs, as exemplified by the mupirocin used for the treatment of staphylococcal infection (4).…”

Self-immunity guided identification of threonyl-tRNA synthetase as the molecular target of obafluorin, a β-lactone antibiotic

“…18 Although ubiquitous, divergence in aaRS sequence structure has led to the evolution of NP antibiotics that selectively target those of competing organisms. 19,20 In a number of instances, a self-resistance isoform of the target aaRS is encoded within the NP BGC as an addition to the primary housekeeping copy encoded elsewhere in the genome of the producing-organism. [21][22][23] Indeed, the putative oba BGC-associated ThrRS homologues all represent second copies in their respective genomes and, likewise, an additional copy of ThrRS is only observed in the presence of the oba BGC amongst these genera.…”

“…aaRSs are attractive therapeutic targets, due to their essential role in translation and the potential to exploit divergences in prokaryotic and eukaryotic forms to generate selective drugs. 19,20 aaRS-targeting natural products have been applied in both crop protection and clinical use, with the LeuRS inhibitor Agrocin TM84 used to treat crown gall disease 32 and the IleRS inhibitor mupirocin used topically in humans to treat skin infections. 33 A variety of mechanisms for aaRS inhibition have been reported, with compounds targeting any of the amino acid, ATP or tRNA subsites within the enzyme, as well as the tRNA substrate itself.…”

Cervicovaginal Microbiome and Urine Metabolome Paired Analysis Reveals Niche Partitioning of the Microbiota in Patients with Human Papilloma Virus Infections

“…Prolyl-tRNA synthetase and threonyl-tRNA synthetase are members of the aminoacyl-tRNA synthetases family, participating in the process of charging a cognate amino acid to tRNA. However, aminoacyl-tRNA synthetases are not only known for their canonical role in protein synthesis but are also involved in a variety of non-canonical processes [46]. Therefore, targeting aminoacyl-tRNA could emerge as a strategy to not only combat cancer but also for managing microbial [47] or parasite infections [48].…”