Inhibitor Of tryptophanyl-tRNA Synthetase Research Articles

Design, synthesis, and antibacterial activity of derivatives of Tryptophanyl-tRNA synthetase inhibitor indolmycin

In this study, indlomycin, an inhibitor of tryptophanyl-tRNA synthetase (TrpRS), and 29 racemic indolmycin derivatives were synthesized, their antibacterial activity were evaluated against methicillin-resistant Staphylococcus aureus (S. aureus) NRS384, ATCC29213, and Escherichia coli (E. coli) ATCC25922 strains. Compounds (±)-7a, (±)-7b, (±)-7c and (±)-7e exhibited minimum inhibitory concentration (MIC) values of 1–2 μg/mL against S. aureus NRS384 and ATCC29213, exhibiting significant antibacterial activity, but none of the compounds exhibited antibacterial activity against E. coli. To investigate the effect of conformation on antibacterial activity, seven racemic compounds with good antibacterial activity were separated, and the antibacterial activity of these 14 compounds was evaluated on 25 bacterial strains. This revealed that the isomers with natural conformations (1′R, 5S) had significantly better antibacterial activity than the enantiomeric isomers and racemates. Compounds 7aa, 7ba, 7ca, and 7ea exhibited good antibacterial activity against 21 strains of S. aureus and S. epidermidis with MIC values of 0.125–2 μg/mL, which were superior to that of vancomycin, used in clinical practice. The compounds 7aa, 7ba, 7ca and 7ea were moderately bound to plasma proteins and were stable in the whole blood of CD-1 mice. In conclusion, a series of new indomycin derivatives with stronger antibacterial activity against G+ bacteria were obtained.

Discovery of indolyl-containing peptides as novel antibacterial agents targeting tryptophanyl-tRNA synthetase.

Background: There is an urgent need for antibiotics with novel structures and unexploited targets to counteract bacterial resistance. Methodology & results: Novel tryptophanyl-tRNA synthetase inhibitors were discovered based on virtual screening, surface plasmon resonance binding, enzymatic activity assay and antibacterial activity evaluation. Of the 29 peptide derivatives tested for antibacterial activity, some inhibited the growth of both Staphylococcus aureus and Staphylococcus epidermidis. A13 and A15 exhibited antibacterial activity against methicillin-resistant S. aureus NRS384 at an 8μg/ml minimum inhibitory concentration. A13 snugly docked into the active site, explaining its improved inhibitory activity. Conclusion: Our results provide us with new structural clues to develop more potent tryptophanyl-tRNA synthetase inhibitors and lay a solid foundation for future drug design efforts.

Design and synthesis of novel spirooxindole-indenoquinoxaline derivatives as novel tryptophanyl-tRNA synthetase inhibitors.

In the current study, we used an integrated approach combining bioinformatics, rational drug design, one-pot synthesis, and biological experiments in vitro for the potential discovery of novel tryptophanyl-tRNA synthetase (TrpRS) inhibitors. Atom economic and diastereoselective syntheses were used to generate several Spirooxindole-indenoquinoxaline derivatives in situ from isatin and amino acids viz. proline, phenylglycine, and sarcosine through targeting the 1,3-dipolar cycloaddition of azomethine ylides. These compounds were assayed by biochemical TrpRS inhibition, using in vitro experiments to test against various gram-positive and gram-negative strains, and using diffuse large B cell lymphoma (DLBCL) cell lines. Compound 6e was found to be the most active in vitro with IC50 values of 225 and 74nM for tests against hmTrpRS and ecTrpRS, respectively. We also found a MIC90 value of 4µg/mL for tests against S. aureus and IC50 values which ranged from 2.9 to 4.8µM for tests against proliferation of DLBCL cell lines. Moreover, compound 6e was remarkably good at inducing bacterial autolysis in MRSA strains. Our results suggested that such an integrated approach could be an attractive and viable strategy for the discovery of novel TrpRS inhibitors as potential lead compounds for antibiotics and as novel anticancer agents. Discovery of novel spirooxindole-indenoquinoxaline TrpRS inhibitors as potential lead compounds with antibacterial and antitumor activities.

Antioxidant activity and antibacterial evaluation of new thiazolin-4-one derivatives as potential tryptophanyl-tRNA synthetase inhibitors

The rapid emergence of bacterial resistance to antibiotics currently available for treating infectious diseases requires effective antimicrobial agents with new structural profiles and mechanisms of action. Twenty-three thiazolin-4-one derivatives were evaluated for their antibacterial activity by determining the growth inhibition zone diameter, the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC), against gram-positive and gram-negative bacteria. Compounds 3a–c, 3e–h, 6b–c and 9a–c expressed better MIC values than moxifloxacin, against Staphylococcus aureus. Compounds 3h and 9b displayed similar effect to indolmycin, a tryptophanyl-tRNA ligase inhibitor. Due to their structural analogy to indolmycin, all compounds were subjected to molecular docking on tryptophanyl-tRNA synthetase. Compounds 3a–e, 6a–e, 8 and 9a–e exhibited better binding affinities towards the target enzymes than indolmycin. The antioxidant potential of the compounds was evaluated by four spectrophotometric methods. Thiazolin-4-ones 3e, 6e and 9e presented better antiradical activity than ascorbic acid, trolox and BHT, used as references.

Chaperon-like Activation of Serum-Inducible Tryptophanyl-tRNA Synthetase Phosphorylation through Refolding as a Tool for Analysis of Clinical Samples

Tryptophanyl-tRNA synthetase (TrpRS) expression alters in colorectal (CRC), pancreatic (PC), and cervical (CC) cancers. Here, phosphorylation of unfolded TrpRS and its fragments is stimulated by human cancer sera (CS; n = 13) and serum of rabbit tumor induced by Rous sarcoma virus, unaffected by donor sera (NS; 11/15) and abolished by alkaline phosphatase. At 20 years of follow-up, serum-inducible TrpRS phosphorylation found years before healthy donors (3/15) diagnosed with PC, CRC, or leukemia. I have examined a specificity of serum-inducible TrpRS phosphorylation and found, surprisingly, that serine phosphorylation of unfolded TrpRS is stimulated by anti-TrpRS rabbit antisera but is unaffected by rabbit nonimmune sera and antisera to other antigens. Anti-TrpRS immunoglobulin G (IgG) inhibits phosphorylation of full-length TrpRS and stimulates phosphorylation of its 20-kDa fragment. Phosphorylation of this fragment is stimulated also by CS but not NS. 2-Mercaptoethanol and cyclic AMP exerted synergistic inhibitory effect on TrpRS phosphorylation. Anti-TrpRS sera and casein act as chaperones increasing TrpRS phosphorylation through refolding. Histone-specific protein kinase activity in CS (n = 44) and anti-TrpRS sera was lower than that in NS (n = 11), rabbit nonimmune sera and antisera to other antigens. TrpRS inhibitors, tryptamine, and tryptophanol stimulate in vivo accumulation of enzymatically inactive, nonphosphorylated, aggregated and anti-TrpRS IgG refoldable TrpRS. Phosphorylation of postsurgical tissues (n = 18) reveals TrpRS in ovarian cancer (OVC) and CC but not in normal placenta and liver. In OVC, TrpRS phosphorylation increase correlates with elevated tryptophan-dependent ATP-inorganic pyrophosphate exchange. Although not inducing cancer, TrpRS triggers signaling concomitant with cancer.

ChemInform Abstract: Structure‐Activity Dependency of New Bacterial Tryptophanyl tRNA Synthetase Inhibitors.

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Structure-activity dependency of new bacterial tryptophanyl tRNA synthetase inhibitors

Analogues of the aminoacyl tRNA synthetase inhibitor, indolmycin, have been synthesised in which the side chain methyl group is replaced by a wide range of substituents. Their antibacterial and enzyme inhibitory potency is related to steric properties and conformational preferences.

The interaction of tryptophanyl-tRNA synthetase with the triazine dye Brown MX-5BR.

Brown MX-5BR specifically and irreversibly inactivates tryptophanyl-tRNA synthetase from Bacillus stearothermophilus at pH 8.5. The enzyme is protected from inactivation by the substrates tryptophan and ATP and to lesser extents by ADP, AMP, the product inorganic pyrophosphate and other nucleotides such as GTP. The Kd of the pure reactive dye for the enzyme was measured to be 6.7 X 10(-6) M. The Km values of the two substrates tryptophan and MgATP were found to be 1 x 10(-5) M and 5 x 10(-5) M respectively. The aminated dye is a competitive inhibitor of tryptophanyl-tRNA synthetase with respect to both tryptophan and MgATP with Ki values of 2 x 10(-4) M against both substrates. The use of this dye as an active-site-directed affinity label is discussed.