The pyrimidine core formed hydrogen bonds with the main chain of Ser266 as well as water-mediated contacts through the lactam carbonyl group to Asp480 (Fig. Structural characterization of ligands showed them to bind in the adenosine pocket, stacked between the side chains of Phe269 and Arg481 (Fig. The observed improvement in potency was enough to allow the first compound/protein structures to be obtained, following soaking of ligands into Apo crystals. Initial SAR exploration for the series: exchanging the pyrimidine for a pyridine, expansion of the cyclopentyl to cyclohexyl, and replacement of the H in the 4-position with F ( 2) were all tolerated and improved potency, although with no selectivity over the human ortholog KARS1 (Fig. The C-terminal catalytic domain (residues 151–505) consists of a largely antiparallel beta-sheet flanked by alpha helices, typical of class II aminoacyl-tRNA synthetases. tuberculosis LysRS consists of an N-terminal anticodon binding domain (residues 1–150) with the typical oligonucleotide binding fold, common to lysyl-, asparaginyl- and aspartyl- tRNA synthetases, consisting of a central six-stranded beta-barrel with loops or alpha helices connecting the strands. tuberculosis LysRS was solved (Supplementary Figure 1A) so that the series could be advanced as an SBDD program. To assist in the understanding of the structure-activity relationships (SAR) and aid computational design approaches, the first crystal structure of M. tuberculosis LysRS it also had modest activity (IC 50 43 µM), comparable to its MIC potency. tuberculosis LysRS with a starting point that was already known to have antibacterial activity. Consequently, 1 represented an opportunity to pursue a target-based drug discovery program against M. tuberculosis the lysyl-tRNA synthetase gene (lysS) is essential 11. Inhibitors of malarial lysyl-tRNA synthetase, including the natural product cladosporin, are potent inhibitors of Plasmodium falciparum growth 9, 10. This class of enzyme uses ATP, to ligate the amino acid lysine to its uncharged tRNA, making lysyl-tRNA available for use by the protein synthesis machinery. While this level of potency did not warrant follow-up itself, the hit remained of interest because, simultaneously, 1 was identified in a screen against malarial lysyl-tRNA synthetase (IC 50 5 µM). ![]() One hit compound ( 1) had a modest IC 50 of ~20 µM in two media that equated to a minimum growth inhibitory concentration (MIC) of 40 µM (Fig. Identification of a series targeting lysyl-tRNA synthetaseĪ growth inhibitory phenotypic screen of the Global Health Chemical Diversity Library (~70,000 compounds) was performed against M. DDD02049209 the lead compound from the series has now entered early toxicity studies, towards declaration as a preclinical development candidate. ![]() Mode of action studies indicate that the compounds from the series are killing M tuberculosis by targeting LysRS in cells. A crystal structure of the protein and the associated structure-based drug discovery (SBDD) program is reported. ![]() tuberculosis lysyl-tRNA synthetase (LysRS). In this report, the identification of a translational inhibitor series is described, targeted against M. Additionally, GSK3036656, an oxaborole that works by covalently binding to the editing site on leucyl-tRNA synthetase, has entered clinical trials 7, 8. The oxazolidinone linezolid, which also targets bacterial ribosomes, was approved in a combination treatment against extensively drug-resistant (XDR) tuberculosis 6. Aminoglycosides, targeting bacterial ribosomes, have until recently been a mainstay of multi-drug-resistant (MDR) tuberculosis treatment 5. Protein synthesis has long been a rich vein for the identification of novel anti-infective agents. There is still an urgent need for new agents to treat tuberculosis, to increase the arsenal of weapons available to combat rising clinical drug resistance, and to shorten the length of treatment. Covid-19 is making the prevalence of tuberculosis worse, due to disrupted routine screening programs leading to reduced detection and a resultant impact in increased deaths 2, 3, 4. Prior to the Covid-19 pandemic, tuberculosis was the world’s leading infectious disease killer, resulting in 1.4 million deaths in 2019 1. Nature Communications volume 13, Article number: 5992 ( 2022) Lysyl-tRNA synthetase, a target for urgently needed M.
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